This document discusses the significance of HLA mismatches in cord blood transplantation and the implications of donor-specific anti-HLA antibodies. It summarizes several studies that have found:
1) Transplants with mismatches only in the graft-versus-host direction have faster engraftment and less transplant-related mortality and treatment failure compared to bidirectional mismatches or mismatches only in the host-versus-graft direction.
2) Patients who are homozygous at a mismatched HLA locus have anti-HLA antibodies reactive with more antigens, increasing the risk of graft failure if donor-specific antibodies are present.
3) The presence of donor-specific anti-HLA antibodies is associated with significantly higher rates
Donor Selection: Sibling. Prof Miguel A Sanzspa718
Miguel A Sanz is a professor of oncology, hematology, and bone marrow transplant in Valencia, Spain. He discusses donor selection considerations when an HLA-matched sibling donor is available for hematopoietic cell transplantation. Younger donor age is preferred, as is matching donor and recipient CMV status. Male donors and nulliparous female donors may be associated with less graft-versus-host disease. Minor ABO mismatches are acceptable, while peripheral blood is now preferred over bone marrow as the stem cell source due to faster engraftment, except in diseases with very low relapse risk.
Transplant in pediatrics in Acute lymphoblastic Luekemia in CR1Dr. Liza Bulsara
to transplant or not to transplant pediatric luekemia in CR1 Has also been a controversial topic . here we give clear recommendation to transplant in difeerent biology group
TA-GVHD is a rare but serious complication of blood transfusions where donor T lymphocytes proliferate in immunocompromised recipients, see the recipient's HLA as foreign, and cause tissue damage. It most often affects those with lymphopenia, immunodeficiencies, or partial HLA matching to donors. Clinical presentation includes rash, diarrhea, hepatitis, and pancytopenia. Diagnosis involves biopsy and HLA testing. Prevention through universal leukoreduction and pathogen inactivation techniques is key as treatment response is poor and mortality is over 90%.
Hematopoietic stem cell transplantation involves intravenous infusion of stem cells collected from bone marrow, peripheral blood, or umbilical cord blood to reestablish hematopoietic function in patients with damaged bone marrow or immune systems. It is potentially curative for various disorders. Stem cells are collected via bone marrow harvest or apheresis and may be manipulated before infusion. Complications can include mucositis, sinusoidal obstructive syndrome, and graft-versus-host disease.
This study assessed the thrombotic risk during oral contraceptive use and pregnancy in 798 female relatives with heterozygous, double heterozygous, or homozygous factor V Leiden or prothrombin mutation from 4 family cohorts. The overall absolute venous thromboembolism (VTE) risk in women with no, single, or combined defects was 0.13, 0.35, and 0.94 per 100 person-years, respectively, while during oral contraceptive use the risks were 0.19, 0.49, and 0.86 per 100 person-years. The risks were highest during pregnancy and postpartum, at 0.73, 1.97, and 7.65 per
This document discusses aplastic anemia and infections in patients undergoing stem cell transplantation (SCT) or immunosuppressive therapy (IST) for aplastic anemia in India. It notes that true incidence of aplastic anemia in India is unknown but it is more common in Asia than the West. For patients under 40, SCT from a HLA-matched sibling donor is the treatment of choice. However, late referrals and financial constraints can increase morbidity and mortality during SCT and IST in India due to less effective first-line treatments, recurrent transfusions, and infections. The document provides data on outcomes of various transplantation approaches and immunosuppressive therapies for aplastic anemia at Christian Medical College, Vello
This document summarizes a study that analyzed antigen expression patterns in different subtypes of myelodysplastic syndromes (MDS) using flow cytometry. Bone marrow samples from 30 newly diagnosed MDS patients classified as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or refractory anemia with excess blasts (RAEB) were analyzed for antigen expression on granulocytic, monocytic, erythroid and lymphoid lineages. The study found no significant differences in antigen expression between subtypes for granulocytic lineages. For erythroid lineages, the percentage of CD71-positive cells was significantly lower in RAEB compared to R
The document discusses hematopoietic stem cell transplantation (HSCT), including opportunities and challenges. It covers various diseases treatable with HSCT, sources of stem cells, factors influencing transplant success, and challenges in finding HLA-matched unrelated donors due to extensive HLA diversity. It proposes establishing stem cell banks with HLA-homozygous embryonic stem cell lines to increase donor availability and success rates for patients requiring HSCT.
Donor Selection: Sibling. Prof Miguel A Sanzspa718
Miguel A Sanz is a professor of oncology, hematology, and bone marrow transplant in Valencia, Spain. He discusses donor selection considerations when an HLA-matched sibling donor is available for hematopoietic cell transplantation. Younger donor age is preferred, as is matching donor and recipient CMV status. Male donors and nulliparous female donors may be associated with less graft-versus-host disease. Minor ABO mismatches are acceptable, while peripheral blood is now preferred over bone marrow as the stem cell source due to faster engraftment, except in diseases with very low relapse risk.
Transplant in pediatrics in Acute lymphoblastic Luekemia in CR1Dr. Liza Bulsara
to transplant or not to transplant pediatric luekemia in CR1 Has also been a controversial topic . here we give clear recommendation to transplant in difeerent biology group
TA-GVHD is a rare but serious complication of blood transfusions where donor T lymphocytes proliferate in immunocompromised recipients, see the recipient's HLA as foreign, and cause tissue damage. It most often affects those with lymphopenia, immunodeficiencies, or partial HLA matching to donors. Clinical presentation includes rash, diarrhea, hepatitis, and pancytopenia. Diagnosis involves biopsy and HLA testing. Prevention through universal leukoreduction and pathogen inactivation techniques is key as treatment response is poor and mortality is over 90%.
Hematopoietic stem cell transplantation involves intravenous infusion of stem cells collected from bone marrow, peripheral blood, or umbilical cord blood to reestablish hematopoietic function in patients with damaged bone marrow or immune systems. It is potentially curative for various disorders. Stem cells are collected via bone marrow harvest or apheresis and may be manipulated before infusion. Complications can include mucositis, sinusoidal obstructive syndrome, and graft-versus-host disease.
This study assessed the thrombotic risk during oral contraceptive use and pregnancy in 798 female relatives with heterozygous, double heterozygous, or homozygous factor V Leiden or prothrombin mutation from 4 family cohorts. The overall absolute venous thromboembolism (VTE) risk in women with no, single, or combined defects was 0.13, 0.35, and 0.94 per 100 person-years, respectively, while during oral contraceptive use the risks were 0.19, 0.49, and 0.86 per 100 person-years. The risks were highest during pregnancy and postpartum, at 0.73, 1.97, and 7.65 per
This document discusses aplastic anemia and infections in patients undergoing stem cell transplantation (SCT) or immunosuppressive therapy (IST) for aplastic anemia in India. It notes that true incidence of aplastic anemia in India is unknown but it is more common in Asia than the West. For patients under 40, SCT from a HLA-matched sibling donor is the treatment of choice. However, late referrals and financial constraints can increase morbidity and mortality during SCT and IST in India due to less effective first-line treatments, recurrent transfusions, and infections. The document provides data on outcomes of various transplantation approaches and immunosuppressive therapies for aplastic anemia at Christian Medical College, Vello
This document summarizes a study that analyzed antigen expression patterns in different subtypes of myelodysplastic syndromes (MDS) using flow cytometry. Bone marrow samples from 30 newly diagnosed MDS patients classified as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or refractory anemia with excess blasts (RAEB) were analyzed for antigen expression on granulocytic, monocytic, erythroid and lymphoid lineages. The study found no significant differences in antigen expression between subtypes for granulocytic lineages. For erythroid lineages, the percentage of CD71-positive cells was significantly lower in RAEB compared to R
The document discusses hematopoietic stem cell transplantation (HSCT), including opportunities and challenges. It covers various diseases treatable with HSCT, sources of stem cells, factors influencing transplant success, and challenges in finding HLA-matched unrelated donors due to extensive HLA diversity. It proposes establishing stem cell banks with HLA-homozygous embryonic stem cell lines to increase donor availability and success rates for patients requiring HSCT.
Association of the HLA-B alleles with carbamazepine-induced Stevens–Johnson s...UniversitasGadjahMada
Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN.We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sundanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2–33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78; 95% CI: 1.96– 23.38). These findings support the involvement of HLA-B*15:02 in CBZ-induced SJS/TEN reported in other Asian populations. Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90–75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83–40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.
Hematopoietic Stem Cells Transplantation for Multiple MyelomaWan Ning
Hematopoietic stem cells transplantation is a FDA-approved stem cells based therapy whereby it is usually performed for cancer patients. For an example, Multiple Myeloma.
This document summarizes key information about chronic lymphocytic leukemia (CLL) including its invisible, inconclusive, and incurable nature at diagnosis. It notes that CLL is often asymptomatic at diagnosis but can have an aggressive clinical course over time, reflecting underlying biological heterogeneity. While treatment has progressed, CLL remains incurable. The document discusses CLL diagnosis and treatment timing and changes in the host and tumor over time. It provides background on CLL occurring in mature B cells and the importance of signaling pathways. The document summarizes prognostic factors in CLL including genetics, mutations, and biomarkers from the tumor and microenvironment. It notes the importance of biological risk stratification and targeting signaling pathways in CLL treatment.
- Allogeneic stem cell transplantation (allo-SCT) remains the recommended treatment for patients with blast crisis CML and those in accelerated phase who do not achieve an optimal response to tyrosine kinase inhibitors (TKIs).
- For patients who experience failure or intolerance to two or more TKIs in chronic phase, allo-SCT is also recommended if they are eligible.
- Outcomes of allo-SCT have improved over time due to advances in reduced intensity conditioning regimens, graft-versus-host disease prophylaxis, and post-transplant maintenance therapies including TKIs and donor lymphocyte infusions.
1) The study found that the Plasmodium yoelii malaria parasite preferentially infects young red blood cells (RBCs) that express high levels of CD47.
2) Mice lacking CD47 (CD47-/- mice) were highly resistant to P. yoelii infection and developed a 9.3-fold lower peak parasitemia compared to wild-type mice.
3) Macrophages from CD47-/- mice were more effective at phagocytizing parasitized RBCs during acute infection, when parasitemia was rapidly rising, suggesting CD47 helps the parasite evade immune clearance.
- The document summarizes a study of 68 children with hereditary spherocytosis (HS).
- The main findings were that the median age at diagnosis was 5.6 years, the most common clinical manifestations were anemia in 59 patients, splenomegaly in 49 patients, and jaundice in 33 patients.
- Laboratory tests including complete blood count, blood smear, and osmotic fragility test were used to diagnose HS.
This document analyzes the incidence, characteristics, and prognosis of acute myeloid leukemia (AML) cases with 11q23 abnormalities involving the MLL gene, as defined by the World Health Organization classification. In an analysis of 1897 cytogenetically analyzed AML cases, the incidence of MLL rearrangements was 2.8%. MLL rearrangements were more common in therapy-related AML, in patients under 60 years old, and in AML subtypes M4, M5a, and M5b. AML with MLL rearrangements had a worse prognosis than AML with intermediate risk cytogenetics but a similar prognosis to those with unfavorable cytogenetics. The median overall survival was significantly better
This document discusses directions and issues in the treatment of acute myeloid leukemia (AML). It addresses challenging existing treatment dogmas regarding chemotherapy drug doses and post-remission therapies. Specifically, it summarizes several studies investigating optimal dose levels of cytarabine and anthracyclines during induction and consolidation for AML. It also reviews evidence comparing the effectiveness of autologous stem cell transplantation versus chemotherapy alone as post-remission consolidation approaches. The document advocates moving beyond conventional chemotherapy regimens to more personalized precision medicine approaches for AML patients.
This study evaluated the efficacy and toxicity of the Hyper-CVAD regimen in treating adult acute lymphocytic leukemia (ALL). 204 adult patients with newly diagnosed ALL received alternating cycles of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and high-dose methotrexate and cytarabine, along with central nervous system prophylaxis and supportive care. Results showed that 91% of patients achieved complete remission and the 5-year survival and complete remission rates were 39% and 38% respectively, demonstrating superior outcomes compared to previous regimens. The Hyper-CVAD regimen was found to be an effective therapy for adult ALL that
Genetic Testing (Eastern Biotech & Life Sciences)Pankaj Sohaney
The document discusses various genetic diagnostic tests including cytogenetic tests, molecular tests, and molecular diagnostics for infectious diseases and genetic identification. It describes tests for genetic diseases including somatic rearrangements in cancer, genetic risk factors, pharmacogenetics, and mutations in monogenic diseases. Specific tests and diseases are discussed, along with factors that impact diagnosis such as disease mutations, technology, cost, and organization.
This study analyzed the prevalence of anemia in 758 HIV-infected patients receiving care at a single public health clinic in 2000. The key findings were:
1) The overall prevalence of anemia (hemoglobin <12.5 g/dL) was 30.3%. Anemia was more common in females (54%) than males (20.2%).
2) Risk factors for anemia included black race, CD4 count <50 cells/μL, viral load >100,000 copies/mL, and use of zidovudine-containing antiretroviral regimens.
3) The majority (67%) of patients who experienced anemia had mild to moderate an
Allogeneic hematopoietic stem cell transplantation (allo HSCT) from an HLA-matched related donor provides the most potent anti-leukemic effect of any post-remission therapy in AML, as demonstrated by the lowest rates of relapse.
Graft vs leukemia plays and important role here.
Provides the best chance of long-term survival
This document discusses hematopoietic stem cell transplantation (HSCT) and its current state and future opportunities. HSCT is an effective treatment for hematologic, immune, metabolic and cancerous diseases. It replaces defective cells and offers high-dose therapy and graft-versus-tumor effects. While HSCT faces challenges like toxicity and costs, advances in unrelated donor matching, cord blood use, and reduced intensity regimens have expanded its applications. Standards and accreditation are needed to ensure quality, and further growth depends on expanded donor availability and combining HSCT with new cellular immunotherapies.
Современное лечение ВИЧ: лечение многократно леченных пациентов с резистентно...hivlifeinfo
This document discusses management of HIV in heavily treatment-experienced patients with multiclass resistance and limited treatment options. It provides an overview of the problem, including that some older patients were treated early in the HIV epidemic with less potent regimens, resulting in resistance. Younger patients may have congenital HIV and been treated long-term. Assessment of virologic failure and resistance testing are important to select an effective new regimen. Current options for active drugs in these patients include maraviroc, ibalizumab, fostemsavir, and enfuvirtide, which have novel mechanisms of action. Adherence assessment is also critical to determine if the current regimen may still be effective if taken as prescribed.
This study investigated whether changes in complement regulatory proteins (CD55 and CD59) on red blood cells contributes to malaria-induced anemia. The study found:
1) Levels of CD55 and CD59 decreased with increased red blood cell age.
2) CD55 levels were lower in children with malaria-induced anemia compared to non-anemic children, and this difference was seen across all red blood cell age groups.
3) CD55 levels correlated positively with hemoglobin levels in anemic children, but CD59 levels did not.
4) The extensive and early loss of CD55 from red blood cells of all ages in malaria-induced anemia, as well as
C4d positivity in Renal transplant rejectionimrana tanvir
This document discusses C4d positivity in renal transplant rejection. It begins by introducing antibody-mediated rejection (AMR) and the classification of AMR. It describes the role of C4d as a marker in transplant rejection and reviews the pros and cons of using C4d. Donor specific antibodies (DSA) are also discussed. Alternative markers to C4d are emerging from genomics and endothelial transcripts. The document concludes by addressing some limitations of C4d and developments in other biomarkers for AMR.
A Peripheral Blood Diagnostic Test for Acute Rejection in renal transplantati...Kevin Jaglinski
This study aimed to develop a non-invasive blood test to diagnose acute renal allograft rejection (AR) after kidney transplantation. Researchers analyzed gene expression in peripheral blood samples from kidney transplant recipients paired with contemporary kidney biopsy results. They identified a set of 5 genes that accurately classified AR in two independent validation sets with over 90% sensitivity and specificity. This 5-gene signature differentiated AR from stable transplant function and other non-AR conditions. The results support further prospective validation of this blood-based diagnostic tool to potentially avoid invasive kidney biopsies for rejection monitoring.
Linda Cendales Composite Tissue Graft Summary Banff 2013 Meeting in BrazilKim Solez ,
Composite tissue graft summary from 12th Banff Conference on Transplant Pathology from the meeting in Comandatuba-Bahia, Brazil on August 23rd, 2013 http://cybernephrology.ualberta.ca/banff/2013
HLA BASICS AND ROLE IN TRANSPLANT IMMUNOLOGYravi jaiswal
George Snell and Jean Dausset were awarded the 1980 Nobel Prize in Physiology or Medicine for their discoveries concerning the HLA system and its role in organ and histocompatibility. The HLA system refers to human leukocyte antigens, which are proteins found on most cells that help the immune system distinguish the body's own cells from foreign cells. HLA genes are highly polymorphic and play a crucial role in matching donors and recipients in organ transplantation to minimize immune rejection. A closer match between a donor's and recipient's HLA types results in better outcomes after transplantation.
1) Alternative donors for hematopoietic stem cell transplantation (HSCT) include one antigen mismatched unrelated donors, umbilical cord blood, and haploidentical related donors.
2) Outcomes with these alternative donors have improved and in some cases are comparable to matched unrelated donors. Cord blood transplants have less graft-versus-host disease but are associated with slower immune recovery. Haploidentical transplants using post-transplant cyclophosphamide have results similar to matched unrelated donors.
3) Almost all patients in need of HSCT now have a potential donor option given improvements in alternative donors. Further research is still needed to compare outcomes such as graft-versus-host disease, relapse
Association of the HLA-B alleles with carbamazepine-induced Stevens–Johnson s...UniversitasGadjahMada
Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN.We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sundanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2–33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78; 95% CI: 1.96– 23.38). These findings support the involvement of HLA-B*15:02 in CBZ-induced SJS/TEN reported in other Asian populations. Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90–75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83–40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.
Hematopoietic Stem Cells Transplantation for Multiple MyelomaWan Ning
Hematopoietic stem cells transplantation is a FDA-approved stem cells based therapy whereby it is usually performed for cancer patients. For an example, Multiple Myeloma.
This document summarizes key information about chronic lymphocytic leukemia (CLL) including its invisible, inconclusive, and incurable nature at diagnosis. It notes that CLL is often asymptomatic at diagnosis but can have an aggressive clinical course over time, reflecting underlying biological heterogeneity. While treatment has progressed, CLL remains incurable. The document discusses CLL diagnosis and treatment timing and changes in the host and tumor over time. It provides background on CLL occurring in mature B cells and the importance of signaling pathways. The document summarizes prognostic factors in CLL including genetics, mutations, and biomarkers from the tumor and microenvironment. It notes the importance of biological risk stratification and targeting signaling pathways in CLL treatment.
- Allogeneic stem cell transplantation (allo-SCT) remains the recommended treatment for patients with blast crisis CML and those in accelerated phase who do not achieve an optimal response to tyrosine kinase inhibitors (TKIs).
- For patients who experience failure or intolerance to two or more TKIs in chronic phase, allo-SCT is also recommended if they are eligible.
- Outcomes of allo-SCT have improved over time due to advances in reduced intensity conditioning regimens, graft-versus-host disease prophylaxis, and post-transplant maintenance therapies including TKIs and donor lymphocyte infusions.
1) The study found that the Plasmodium yoelii malaria parasite preferentially infects young red blood cells (RBCs) that express high levels of CD47.
2) Mice lacking CD47 (CD47-/- mice) were highly resistant to P. yoelii infection and developed a 9.3-fold lower peak parasitemia compared to wild-type mice.
3) Macrophages from CD47-/- mice were more effective at phagocytizing parasitized RBCs during acute infection, when parasitemia was rapidly rising, suggesting CD47 helps the parasite evade immune clearance.
- The document summarizes a study of 68 children with hereditary spherocytosis (HS).
- The main findings were that the median age at diagnosis was 5.6 years, the most common clinical manifestations were anemia in 59 patients, splenomegaly in 49 patients, and jaundice in 33 patients.
- Laboratory tests including complete blood count, blood smear, and osmotic fragility test were used to diagnose HS.
This document analyzes the incidence, characteristics, and prognosis of acute myeloid leukemia (AML) cases with 11q23 abnormalities involving the MLL gene, as defined by the World Health Organization classification. In an analysis of 1897 cytogenetically analyzed AML cases, the incidence of MLL rearrangements was 2.8%. MLL rearrangements were more common in therapy-related AML, in patients under 60 years old, and in AML subtypes M4, M5a, and M5b. AML with MLL rearrangements had a worse prognosis than AML with intermediate risk cytogenetics but a similar prognosis to those with unfavorable cytogenetics. The median overall survival was significantly better
This document discusses directions and issues in the treatment of acute myeloid leukemia (AML). It addresses challenging existing treatment dogmas regarding chemotherapy drug doses and post-remission therapies. Specifically, it summarizes several studies investigating optimal dose levels of cytarabine and anthracyclines during induction and consolidation for AML. It also reviews evidence comparing the effectiveness of autologous stem cell transplantation versus chemotherapy alone as post-remission consolidation approaches. The document advocates moving beyond conventional chemotherapy regimens to more personalized precision medicine approaches for AML patients.
This study evaluated the efficacy and toxicity of the Hyper-CVAD regimen in treating adult acute lymphocytic leukemia (ALL). 204 adult patients with newly diagnosed ALL received alternating cycles of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and high-dose methotrexate and cytarabine, along with central nervous system prophylaxis and supportive care. Results showed that 91% of patients achieved complete remission and the 5-year survival and complete remission rates were 39% and 38% respectively, demonstrating superior outcomes compared to previous regimens. The Hyper-CVAD regimen was found to be an effective therapy for adult ALL that
Genetic Testing (Eastern Biotech & Life Sciences)Pankaj Sohaney
The document discusses various genetic diagnostic tests including cytogenetic tests, molecular tests, and molecular diagnostics for infectious diseases and genetic identification. It describes tests for genetic diseases including somatic rearrangements in cancer, genetic risk factors, pharmacogenetics, and mutations in monogenic diseases. Specific tests and diseases are discussed, along with factors that impact diagnosis such as disease mutations, technology, cost, and organization.
This study analyzed the prevalence of anemia in 758 HIV-infected patients receiving care at a single public health clinic in 2000. The key findings were:
1) The overall prevalence of anemia (hemoglobin <12.5 g/dL) was 30.3%. Anemia was more common in females (54%) than males (20.2%).
2) Risk factors for anemia included black race, CD4 count <50 cells/μL, viral load >100,000 copies/mL, and use of zidovudine-containing antiretroviral regimens.
3) The majority (67%) of patients who experienced anemia had mild to moderate an
Allogeneic hematopoietic stem cell transplantation (allo HSCT) from an HLA-matched related donor provides the most potent anti-leukemic effect of any post-remission therapy in AML, as demonstrated by the lowest rates of relapse.
Graft vs leukemia plays and important role here.
Provides the best chance of long-term survival
This document discusses hematopoietic stem cell transplantation (HSCT) and its current state and future opportunities. HSCT is an effective treatment for hematologic, immune, metabolic and cancerous diseases. It replaces defective cells and offers high-dose therapy and graft-versus-tumor effects. While HSCT faces challenges like toxicity and costs, advances in unrelated donor matching, cord blood use, and reduced intensity regimens have expanded its applications. Standards and accreditation are needed to ensure quality, and further growth depends on expanded donor availability and combining HSCT with new cellular immunotherapies.
Современное лечение ВИЧ: лечение многократно леченных пациентов с резистентно...hivlifeinfo
This document discusses management of HIV in heavily treatment-experienced patients with multiclass resistance and limited treatment options. It provides an overview of the problem, including that some older patients were treated early in the HIV epidemic with less potent regimens, resulting in resistance. Younger patients may have congenital HIV and been treated long-term. Assessment of virologic failure and resistance testing are important to select an effective new regimen. Current options for active drugs in these patients include maraviroc, ibalizumab, fostemsavir, and enfuvirtide, which have novel mechanisms of action. Adherence assessment is also critical to determine if the current regimen may still be effective if taken as prescribed.
This study investigated whether changes in complement regulatory proteins (CD55 and CD59) on red blood cells contributes to malaria-induced anemia. The study found:
1) Levels of CD55 and CD59 decreased with increased red blood cell age.
2) CD55 levels were lower in children with malaria-induced anemia compared to non-anemic children, and this difference was seen across all red blood cell age groups.
3) CD55 levels correlated positively with hemoglobin levels in anemic children, but CD59 levels did not.
4) The extensive and early loss of CD55 from red blood cells of all ages in malaria-induced anemia, as well as
C4d positivity in Renal transplant rejectionimrana tanvir
This document discusses C4d positivity in renal transplant rejection. It begins by introducing antibody-mediated rejection (AMR) and the classification of AMR. It describes the role of C4d as a marker in transplant rejection and reviews the pros and cons of using C4d. Donor specific antibodies (DSA) are also discussed. Alternative markers to C4d are emerging from genomics and endothelial transcripts. The document concludes by addressing some limitations of C4d and developments in other biomarkers for AMR.
A Peripheral Blood Diagnostic Test for Acute Rejection in renal transplantati...Kevin Jaglinski
This study aimed to develop a non-invasive blood test to diagnose acute renal allograft rejection (AR) after kidney transplantation. Researchers analyzed gene expression in peripheral blood samples from kidney transplant recipients paired with contemporary kidney biopsy results. They identified a set of 5 genes that accurately classified AR in two independent validation sets with over 90% sensitivity and specificity. This 5-gene signature differentiated AR from stable transplant function and other non-AR conditions. The results support further prospective validation of this blood-based diagnostic tool to potentially avoid invasive kidney biopsies for rejection monitoring.
Linda Cendales Composite Tissue Graft Summary Banff 2013 Meeting in BrazilKim Solez ,
Composite tissue graft summary from 12th Banff Conference on Transplant Pathology from the meeting in Comandatuba-Bahia, Brazil on August 23rd, 2013 http://cybernephrology.ualberta.ca/banff/2013
HLA BASICS AND ROLE IN TRANSPLANT IMMUNOLOGYravi jaiswal
George Snell and Jean Dausset were awarded the 1980 Nobel Prize in Physiology or Medicine for their discoveries concerning the HLA system and its role in organ and histocompatibility. The HLA system refers to human leukocyte antigens, which are proteins found on most cells that help the immune system distinguish the body's own cells from foreign cells. HLA genes are highly polymorphic and play a crucial role in matching donors and recipients in organ transplantation to minimize immune rejection. A closer match between a donor's and recipient's HLA types results in better outcomes after transplantation.
1) Alternative donors for hematopoietic stem cell transplantation (HSCT) include one antigen mismatched unrelated donors, umbilical cord blood, and haploidentical related donors.
2) Outcomes with these alternative donors have improved and in some cases are comparable to matched unrelated donors. Cord blood transplants have less graft-versus-host disease but are associated with slower immune recovery. Haploidentical transplants using post-transplant cyclophosphamide have results similar to matched unrelated donors.
3) Almost all patients in need of HSCT now have a potential donor option given improvements in alternative donors. Further research is still needed to compare outcomes such as graft-versus-host disease, relapse
Hematopoietic stem cell transplantation involves transplanting stem cells from bone marrow, peripheral blood, or umbilical cord blood to a recipient. There are two main types: autologous transplants using the patient's own stem cells and allogeneic transplants using donor stem cells. Allogeneic transplants from related donors have the best outcomes. The transplant process involves conditioning with chemotherapy and/or radiation, stem cell infusion, a neutropenic phase making the patient susceptible to infection, engraftment as the donor cells establish, and a post-engraftment period monitoring for complications like graft-versus-host disease.
Graft-vs.-Host Disease and Umbilical Cord Transplantationcordbloodsymposium
This document discusses graft-versus-host disease (GVHD) and umbilical cord transplantation. It provides background on umbilical cord blood transplants and their relationship to GVHD. Specifically, it addresses several risk factors for GVHD following umbilical cord transplantation, including the degree of HLA matching between donor and recipient, GVHD prophylaxis regimens, and the use of anti-thymocyte globulin (ATG). The document analyzes studies on these topics and provides evidence that better HLA matching, use of mycophenolate for GVHD prophylaxis, and ATG administration may help reduce the risk of GVHD, though results are mixed.
Ohio State's 2016 ASH Review Blood and Marrow Trasplantation (with Turning Po...OSUCCC - James
Ohio State’s 2016 ASH Review
Blood and Marrow Transplantation
Basem M. William, MD, MRCP(UK), FACP
Assistant Professor of Internal Medicine
Blood and Marrow Transplant Program
Graft-versus-host disease (GVHD) is a complication seen in allogeneic stem cell transplantation. The incidence and severity is more in T-cell replete allograft (stem cells), donor T-cells being the principal mediators of GVHD. Acute GVHD is seen within 90 days post transplant and chronic GVHD after 90 days. Cyclosporin A (CsA) and methotrexate combination is used in prevention of acute GVHD. Corticosteroids and CsA combination is used in treatment of both acute and chronic GVHD.
Journal Reading Stem Cell dengan HIV (sharon) soroylardo1
1) Studies in murine and macaque models show that genetically modifying CD4+ T-cells to disrupt CCR5, the main HIV coreceptor, provides a selective advantage over non-modified cells and significantly reduces plasma viremia. However, a source of residual viral reservoir remains.
2) Two HIV patients who underwent allogeneic stem cell transplantation from CCR5-negative donors have remained virus-free for nearly 4 years after transplantation while kept on antiretroviral therapy (ART), suggesting genetic modification may not be necessary if ART is completely suppressive.
3) Hematopoietic stem cell transplantation remains a promising curative approach for HIV, but the timing of ART interruption
This document discusses hematopoietic stem cell transplantation (HSCT) for various diseases. It provides an overview of HSCT, including its history and advancements. Key topics covered include stem cell sources, transplant types, donor selection criteria, diseases treated, and alternative donors such as unrelated donors and cord blood. The document also discusses graft-versus-host disease and graft-versus-leukemia effect, as well as non-myeloablative conditioning regimens and donor lymphocyte infusions.
This document discusses antibody-mediated rejection (AMR) in organ transplantation and methods for detecting donor-specific antibodies (DSAs).
It first describes how AMR occurs when antibodies react with antigens on vascular endothelium, causing complement activation and vascular damage. Diagnosis requires histologic lesions, detection of C4d factor, and identifying DSAs in serum.
It then discusses different antibody detection methods like panel-reactive antibodies (PRA), Luminex single antigen beads, and crossmatch tests. Flow cytometric crossmatching is more sensitive than CDC crossmatch in detecting low-titer or non-complement-fixing antibodies. Preformed DSAs, especially against HLA Class I and II, increase rejection
When matched family donor is not available for blood and marrow transplantati...Apollo Hospitals
Only 20–30% of patients requiring a blood and marrow transplantation (BMT) have a matched family donor. For the rest, alternative sources of graft are necessary to provide this curative procedure. Over the past 25 years, BMT from volunteer unrelated donors has undergone immense developments to be at par with matched family donor transplants. Similar developments have been witnessed in the field of unrelated cord blood transplantation. Thus, 90% of patients requiring a BMT in the developed worlds receive one from either of the two alternative graft sources. However, >11 million volunteer unrelated donors and 25,000 cord blood units worldwide do not solve the problem for patients from developing countries, due to lack of compatible human leukocyte antigen (HLA) match and enormous financial burden. Thus, Asian countries such as China and Korea have developed Haploidentical or mismatched family donor transplantation for their population with great success. In the light of these developments, this article discusses the options and opportunities for alternative donor BMT in the Indian scenario.
The document describes the design of a customized genome-wide genotyping array ("TxArray") for transplantation studies. It includes approximately 782,000 markers focused on loci related to HLA, KIR, pharmacogenomics, and metabolism that are important for transplantation. Testing on 85 HapMap samples showed high concordance (0.996) and low error rates, and genotype imputation was highly accurate (over 0.962). The array was designed to improve coverage of regions like KIR compared to other platforms and enable large-scale genetic studies in transplant cohorts.
This document discusses stem cell transplantation as a treatment for Mucopolysaccharidosis type 1 (MPS I), also known as Hurler syndrome. MPS I is caused by a deficiency of the IDUA enzyme, leading to a buildup of glycosaminoglycans. Stem cell transplantation provides a source of functional IDUA enzyme and has become the standard treatment for the most severe form, Hurler syndrome. The document reviews several studies that have examined outcomes of stem cell transplantation for MPS I and have found improved long-term survival and reduced morbidity when combined with enzyme replacement therapy prior to transplantation.
Renal transplantation provides better outcomes than dialysis for patients with end-stage renal disease. Candidates are evaluated for medical contraindications and kidney function is assessed in living donors. HLA matching and negative cross-matching between donor and recipient improve graft survival. While immunosuppression carries risks, multidrug regimens can prevent rejection and maximize allograft longevity. Long-term monitoring is needed due to potential complications. Overall, transplantation usually improves quality and length of life for eligible patients with kidney failure.
This document summarizes mixed-phenotype acute leukemia (MPAL), a rare and heterogeneous leukemia with an unclear lineage. MPAL has a poor prognosis overall compared to typical acute myeloid or lymphoblastic leukemia. Emerging evidence suggests that pediatric-inspired ALL regimens may lead to better outcomes for adults aged 18-40 compared to traditional therapies. Allogeneic stem cell transplant after chemotherapy also appears to improve survival compared to chemotherapy alone, though prospective clinical trials are still needed to better guide treatment.
Donor Selection: Unrealted donor transplant. Prof. Richard Champlinspa718
Richard Champlin is a professor and chair of the Department of Stem Cell Transplantation and Cellular Therapy at MD Anderson Cancer Center. He has over 30 years of experience in hematopoietic stem cell transplantation research. In this presentation, he discusses the pros and cons of different stem cell donor sources for transplantation including matched sibling, matched unrelated donor, cord blood, and haploidentical related donors. While matched siblings remain the preferred donor source, innovative strategies are improving outcomes with alternative donor sources like cord blood and haploidentical transplants. Prospective studies are still needed to directly compare outcomes between donor modalities.
1) The study aimed to use the PP65 antigenemia technique to diagnose active cytomegalovirus (CMV) infection in AIDS patients in Brazil and examine its occurrence in the region.
2) They found that 14 of 50 AIDS patients tested positive for PP65 antigenemia, indicating active CMV infection, while none of the 34 bone marrow transplant patients tested positive.
3) Having a CD4+ T-cell count below 100 cells/mm3 appeared to increase the risk of testing positive for PP65 antigenemia and active CMV infection, as more low CD4 count patients tested positive compared to higher CD4 count patients.
2020 Transplant Immunogenicity Calculator : Fiction or Reality? - prof. Ahmed...MNDU net
This document discusses transplant immunogenicity and summarizes several studies on predicting immunogenicity of HLA mismatches. It finds that:
1) Not all HLA antigen mismatches are equally immunogenic, and some provoke stronger rejection responses than others. Some donor-recipient HLA combinations are considered "taboo" as they are highly immunogenic.
2) Studies have identified a potential hierarchy of HLA antigens in terms of immunogenicity, with some like DR5/A2 mismatches associated with worse outcomes.
3) Newer methods using epitope-level analysis like HLAMatchmaker and PIRCHE II can better predict immunogenicity and risk of de novo donor-specific antibodies than serological HLA typing alone
This systematic review analyzed 22 studies reporting on the impact of ABO blood type mismatch on outcomes after hematopoietic stem cell transplantation. The majority of studies found no significant effect of ABO mismatch on overall survival. However, a few studies reported a significant decrease in overall survival, particularly for patients receiving a bidirectional (major and minor) mismatched transplant. The results for other outcomes like graft-versus-host disease and relapse were mixed, with some studies reporting significant effects of ABO mismatch and others finding no effect. The review indicated that the evidence is inconclusive due to contradictory findings across studies.
Similar to The Significance of the Direction of the HLA Mismatch in Cord Blood Matching and the Implication of Graft-Specific Anti-HLA Antibodies (20)
A Potential Global Role for Dipeptidylpeptidase 4 (DPP4/CD26) and Its Inhibit...cordbloodsymposium
This document discusses the potential role of Dipeptidylpeptidase 4 (DPP4/CD26) in regulating hematopoiesis and cell systems. It summarizes research showing that DPP4 truncates cytokines involved in hematopoiesis, reducing their activity. Mice lacking DPP4 had enhanced recovery from radiation/drug stress and better engraftment of transplanted cells. A clinical trial found that giving a DPP4 inhibitor to cord blood transplant recipients improved engraftment rates compared to expected outcomes. The document provides evidence that inhibiting DPP4 can enhance hematopoietic cell transplantation.
Cord blood is a potential source of natural killer (NK) cells for cancer immunotherapy. NK cells can be expanded from cord blood units to sufficient clinical scales for treatment. Expanded cord blood NK cells have been shown to be as cytotoxic against tumors as peripheral blood NK cells. They have demonstrated activity against multiple myeloma and chronic lymphocytic leukemia in preclinical studies. A phase I/II clinical trial is exploring the use of ex vivo expanded cord blood NK cells combined with chemotherapy and autologous stem cell transplant for multiple myeloma. Additional strategies are being investigated to enhance the anti-tumor activity of cord blood NK cells, such as using lenalidomide or engineering the cells to improve homing to the bone marrow micro
Multicenter Study of Third-Party Virus-Specific T cells to Treat Adenovirus, ...cordbloodsymposium
Three sentences:
Banked virus-specific T cells were administered to 45 patients with refractory viral infections after hematopoietic stem cell transplantation. The banked T cells showed low toxicity and were effective in clearing disease for 74% of patients with Epstein-Barr virus, adenovirus, or cytomegalovirus infections. While individualized T cell products remain ideal, this study demonstrates that partially HLA-matched third-party virus-specific T cells can provide clinical benefit for patients in need of immunotherapy for viral infections.
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1) The incidence of autoimmune disease after cord blood transplantation was 6% in this study, with autoimmune hemolytic anemia and immune thrombocytopenia being the most common.
2) Risk factors for developing autoimmune disease after cord blood transplantation included having a non-malignant disease indication and a longer time interval from diagnosis to transplant.
3) Treatment of autoimmune diseases post-transplant included steroids, immunosuppressive therapy, and rituximab, with many patients achieving complete or partial remission.
Expenses as an Issue Inhibiting the Use of Cord Blood Transplantationcordbloodsymposium
This document discusses the costs associated with cord blood transplantation and how they impact its use. It notes that insurance coverage and the time commitment are barriers. The main costs are the cord blood product itself, collection and banking fees, and higher expenses during the medical procedure due to slower engraftment times and potential complications. Suggestions to address these issues include improving education, identifying selection criteria to reduce multi-cord transplants, expanding cord blood units, and making cord blood banking more efficient.
Outcomes Using Single and Double Unit Cord Blood Transplant Graftscordbloodsymposium
This study compared outcomes of single and double unit unrelated cord blood transplantation (UCBT) in adults with acute leukemia in remission using myeloablative conditioning regimens. The study found that neutrophil recovery and grade II-IV acute GVHD rates varied depending on the specific conditioning regimen used for single or double UCBT, but 2-year relapse incidence, 1-year non-relapse mortality, and 2-year overall survival were comparable between single and double UCBT when adequate cell doses were infused. This suggests that survival after transplantation using a single UCBT unit with an adequate cell dose is similar to outcomes after double UCBT for adults with acute leukemia receiving myeloablative conditioning.
Myeloablative Umbilical Cord Blood Transplantation for Hematologic Malignanci...cordbloodsymposium
This study retrospectively analyzed outcomes for 566 patients undergoing hematopoietic stem cell transplantation for hematologic malignancies with either umbilical cord blood (CBT, n=112) or unrelated donor (URD, n=454) transplantation between 2006-2012. Disease free survival, relapse rates, and non-relapse mortality were comparable between CBT and URD recipients. Younger CBT patients had lower mortality risks compared to younger URD patients, but this advantage disappeared in older patients. Relapse was also less frequent after CBT. The risk of chronic graft-versus-host disease was lower for matched unrelated donor bone marrow recipients. Overall, outcomes were not inferior for CBT compared to URD
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This document summarizes the challenges of performing umbilical cord blood transplants in developing countries like India. It notes that while transplant centers are common in the US, India has a growing population of over 1 billion but only conducts around 300 transplants per year. It discusses the limited public and private cord blood banking options in India. The document also reviews clinical data from Apollo Speciality Hospital on matched sibling cord transplants and 3/6 matched unrelated cord transplants. It identifies issues like marketing of private cord banking, standardized cell dosing, and a lack of search coordinators for unrelated transplants. The document concludes by highlighting lessons learned, such as the importance of patient selection and using reduced intensity conditioning, and the need to
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This document discusses the potential role of Dipeptidylpeptidase 4 (DPP4/CD26) in regulating hematopoiesis and cell systems. It summarizes research showing that DPP4 truncates cytokines involved in hematopoiesis, reducing their activity. Mice lacking DPP4 had enhanced recovery from radiation/drug stress and better engraftment of transplanted cells. A clinical trial found that giving a DPP4 inhibitor to recipients of single cord blood transplants improved engraftment rates over expected outcomes. The document provides evidence that inhibiting DPP4 can enhance hematopoietic cell transplantation and recovery from stress.
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This document summarizes results from a study comparing outcomes of haplo-cord stem cell transplantation (SCT) to matched unrelated donor (MUD) SCT in high-risk adult patients. The study found that haplo-cord SCT resulted in similar time to engraftment and survival rates as MUD SCT, with significantly lower rates of graft-versus-host disease. Both approaches resulted in comparable non-relapse mortality and relapse rates. The results suggest haplo-cord SCT is a valuable alternative to MUD SCT for high-risk patients lacking a matched adult donor.
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The document analyzes data from the Eurocord Registry on outcomes of double unit cord blood transplantation, finding that higher pre-freezing CD34+ cell doses were associated with increased neutrophil engraftment and lower transplantation-related mortality, while higher post-thawing CD34+ cell doses were linked to higher engraftment rates; disease status at transplantation also impacted outcomes like disease free survival. The analysis included over 1,100 adult and over 200 pediatric transplants from the Eurocord database.
Double Unit Cord Blood Transplantation for Acute Leukemiacordbloodsymposium
This document summarizes research presented by Dr. Juliet Barker on double unit cord blood transplantation (DCBT) for acute leukemia. The key points are:
1. DCBT aims to augment graft cell dose to improve engraftment, reduce transplant-related mortality, and improve survival rates compared to single unit CBT.
2. Studies at MSKCC and other centers show comparable or improved survival rates for DCBT compared to matched related or unrelated donor transplants.
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4. Research suggests the winning unit is determined by immune
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1) Several studies have found that the presence of donor-specific anti-HLA antibodies (DSA) in cord blood transplant recipients is associated with worse transplant outcomes, including higher rates of graft failure and mortality.
2) The intensity of DSA as measured by mean fluorescent intensity (MFI) correlates with transplant outcomes, with higher MFI DSA generally leading to poorer engraftment and survival.
3) Screening recipients for DSA and avoiding the selection of cord blood units with antigens corresponding to identified DSA is recommended to improve outcomes after cord blood transplantation.
Unrelated Cord Blood Transplantation In Adults with Hematological Malignancie...cordbloodsymposium
This document summarizes research on unrelated cord blood transplantation (UCBT) for adults with hematological malignancies. It provides updates from the Eurocord registry on over 11,000 UCBT cases. It then reviews outcomes from UCBT for specific diseases like acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS). Favorable factors are identified such as disease status, age, and cell dose. Conditioning regimens and complications are also discussed. Surveys of UCBT for ALL and AML provide more detailed analyses of 2-year survival rates based on disease characteristics and transplant factors.
Cord Blood Transplantation: Are the indications changing?cordbloodsymposium
Umbilical cord blood transplantation (UCBT) is an alternative donor source for hematopoietic cell transplantation (HCT). UCBT provides an HLA-mismatched graft option for patients who lack an HLA-matched sibling donor. While UCBT is associated with slower engraftment compared to bone marrow or peripheral blood grafts, UCBT grafts have a lower risk of acute and chronic graft-versus-host disease. Larger studies are still needed to better understand outcomes with UCBT compared to other donor sources and to identify ways to reduce morbidity and improve survival following UCBT.
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Late Outcomes of Cord Blood Transplantation for Patients with Hurler Syndrome
This study analyzed 197 patients with Hurler syndrome who underwent hematopoietic stem cell transplantation between 1980-2008. It found that event-free survival was highest for those receiving stem cells from an identical sibling or 6/6 cord blood match. Neurodevelopmental outcomes and risks of orthopedic complications were influenced by pre-transplant developmental status and enzyme levels post-transplant, indicating residual disease burden remains. Earlier transplantation and strategies to increase post-transplant enzyme levels may further optimize outcomes.
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2) While HSCT can cure SCD by replacing the defective hematopoietic stem cells, current transplant approaches still carry high risks of transplant-related mortality, graft-versus-host disease, and long-term effects on fertility and cognition.
3) Recent efforts aim to reduce the intensity of pre-transplant conditioning to lower toxicity while maintaining graft-versus-host disease prevention. Additional areas of research focus on optim
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This document discusses potential combination therapies for treating globoid cell leukodystrophy (Krabbe disease), a rare genetic disorder. It summarizes that current treatments like bone marrow transplantation and gene therapy have only been partially effective. The document then describes research in a mouse model of the disease that found combining gene therapy with bone marrow transplantation had greater efficacy than either treatment alone. It further notes that adding a third treatment, substrate reduction therapy, provided even further synergistic effects by targeting additional disease mechanisms. The conclusion is that combination therapies targeting multiple aspects of the disease may be needed to significantly improve outcomes for Krabbe patients.
1. The document discusses potential new uses of cord blood beyond current therapeutic uses, including expanding cord blood, identifying other stem cell populations, storing and using placental tissue, and generating induced pluripotent stem cells (iPSCs).
2. It then lists over 70 companies involved in cord blood banking worldwide and their websites.
3. The final section provides details on the process of deriving an iPSC culture from cord blood, including reprogramming, selecting clones, testing for pluripotency and differentiation, and why cord blood banks are a good source for this process.
Deriving Mesenchymal Stem Cells from Human Amniotic Fluid – Potential for an ...cordbloodsymposium
The Wake Forest Institute for Regenerative Medicine has made several breakthroughs in the field of regenerative medicine, including being the first to engineer and implant lab-grown organs in patients. The Institute aims to develop regenerative therapies and has an interdisciplinary team working on engineering over 30 tissues and organs. Recent research at the Institute has focused on stem cells derived from amniotic fluid, which can differentiate into several tissue types and may have potential for treating various diseases.
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The Significance of the Direction of the HLA Mismatch in Cord Blood Matching and the Implication of Graft-Specific Anti-HLA Antibodies
1. 1
The Significance of the Direction of the HLA Mismatch in
Cord Blood Matching and the Implication of Graft-
Specific Anti-HLA Antibodies
Marcelo A. Fernández Viña, Ph.D.
Department of Pathology
Medical School
Stanford University
2. 2
Goals of Allogeneic HSCT
• Achieve Engraftment
• Absence of Graft versus Host Disease
• Prevent Relapse
• Effective Immune reconstitution
4. 44
Factors Influencing Decision to Transplant
Quality of HLA match
Recipient factors
Diagnosis and stage of disease
Age
Major organ function
CMV serology
Donor/CBU factors
Age – Period of collection
Body size - Cell Dose
CMV serology – Infectious Disease Markers
Pregnancy and transfusion history
5. 5
Patient and Donor/CBU are Heterozygous in all HLA loci
Difference (mismatch) in One allele of HLA-A
• The HLA-A mismatched antigen in the Donor/CBU can be recognized as
foreign by the Patient’s Immune System (Host versus Graft; rejection)
• The HLA-A mismatched antigen in the Patient can be recognized as foreign by
the Donor/CBU’s Immune System (Graft versus Host; GvHD and GvL)
33
Molecules encoded in the HLA systemMolecules encoded in the HLA system
Maternal
origin
PATIENT
Encoded in HLA-DRB1
locus
(Class II)
Encoded in HLA-A
locus
(Class I)
Paternal
origin
Encoded in HLA-B
locus
(Class I)
6. 6
Patient is Homozygous in HLA-A and Donor/CBU is
Heterozygous in HLA-A
Mismatch Only in the HvG direction
• The HLA-A mismatched antigen in the Donor/CBU can be recognized as
foreign by the Patient’s Immune System (Host versus Graft; rejection)
• No mismatch in the Graft versus host direction (No Graft versus Host; No
GvHD/ No GvL)
33
Molecules encoded in the HLA systemMolecules encoded in the HLA system
Maternal
origin
DONOR/CBU
Encoded in HLA-DRB1
locus
(Class II)
Encoded in HLA-A
locus
(Class I)
Paternal
origin
Encoded in HLA-B
locus
(Class I)
7. 7
Patient is Heterozygous in HLA-A, Donor/CBU is
Homozygous in HLA-A for one allele present in the Patient
Mismatch Only in the HvG direction
• The HLA-A mismatched antigen in the Patient can be
recognized as foreign by the Donor/CBU ’s Immune
System (Graft versus Host; GvHD and GvL)
• No mismatch int Host versus Graft direction
33
Molecules encoded in the HLA systemMolecules encoded in the HLA system
Maternal
origin
PATIENT
Encoded in HLA-DRB1
locus
(Class II)
Encoded in HLA-A
locus
(Class I)
Paternal
origin
Encoded in HLA-B
locus
(Class I)
8. 8
“HLA mismatch direction in cord blood transplantation: impact on
outcome and implications for cord blood unit selection”
Stevens CE, Carrier C, Carpenter C, Sung D, Scaradavou A
Blood. 2011 Oct 6;118(14):3969-78.
• 1202 single CBU TX
• 1993-2006 (57% before 2000)
• Engraftment at day 77
• 75 % <16 y/o
• 67% Malignancies
• Early (23%), Intermediate
(46%), Advanced 30%)
• 6/6 – 6%
• 5/6 – 38%
• 364 1 bidirectional MM
• 58 GvH-only MM
• 40 HvG-Only MM
• 76% Neutrophil engraftment
• 51 % Platelet engraftment
• Match grade (p<0.001) and cell
dose (p<0.006) changed over
time
• Engraftment Faster in the GvH-
only (HR = 1.6, P = .003)
• GvH-only had Less TRM,
Mortality, Treatment Failure in
patients with Maligancy
• Comparable to Matched
transplants
12. 12
• “Evaluation of HLA matching in unrelated
hematopoietic stem cell transplantation for
nonmalignant disorders”
• John Horan, Tao Wang, Michael Haagenson,
Stephen R. Spellman, Jason Dehn, Mary Eapen,
Haydar Frangoul, Vikas Gupta, Gregory A.
Hale, Carolyn K. Hurley, Susana Marino,
Machteld Oudshoorn, Vijay Reddy, Peter Shaw,
Stephanie J. Lee and Ann Woolfrey
• Blood. 2012 Oct 4;120(14):2918-24.
14. 14
BMT in Non-Malignant Diseases
CBU
• Similar to HSCT in non-Malignant
Diseases, absence of Engraftment may have
played a major role in causing morbidity
and mortality
15. 15
Goals of Allogeneic BMT
Achieve Engraftment:
• Patient’s immune system may cause
rejection
• Donor’s immune system may enhance the
engraftment through the destruction of
patient’s immune cells that cause rejection
16. 16
Histocompatibility Factors
Affecting Engraftment
• HLA-mismatches in the Host versus graft
direction (HvG mismatch)
• Patient’s Homozygosity (HvG mismatch)
• Donor-specific anti-HLA Antibodies
• ABO Major Mismatch
17. 17
Homozygosity at a given locus vs
Heterozygosity
Major-Histocompatibility-Complex class I alleles and antigens in hematopoietic-
cell transplantation.
Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T, Storer
B, Mickelson E, Smith A, Anasetti C.
N Engl J Med. 2001 Dec 20;345(25):1794-800
• CML, No ATG
• RESULTS: A single HLA allele mismatch did not increase the risk of graft
failure, whereas a single antigen mismatch significantly increased the risk
• The risk was also increased if the recipient was HLA homozygous at the
mismatched class I locus or if the donor had two or more class I mismatches
• CONCLUSIONS: HLA class I antigen mismatches that are serologically
detectable confer an enhanced risk of graft failure after hematopoietic-cell
transplantation. Transplants from donors with a single class I allele mismatch that
is not serologically detectable may be used without an increased risk of graft
failure
19. Impact of High Resolution Mismatches (Allele Level) & Broad
Mismatches (Serologically Detectable) in Alleles of HLA Loci
20. 20
The impact of HLA unidirectional mismatches on
the outcome of myeloablative hematopoietic stem
cell transplantation with unrelated donors
• Hurley CK, Woolfrey A, Wang T, Haagenson M,
Umejiego J, Aljurf M, Askar M, Battiwalla M, Dehn J,
Horan J, Oudshoorn M, Pidala J, Saber W, Turner V, Lee
SJ, Spellman S
• Blood. 2013 May 1. [Epub ahead of print] PubMed PMID:
23637130
• 2,687 myeloablative MUD; malignant disease
• 7/8 bidirectional MM transplants, n=1393
• 7/8 host vs. graft (HVG) vector MM , n=112
• 7/8 graft vs. host (GVH) vector MM, n=119
• 8/8 matches, n=1063
21. 21
HvG and GvH mismatches
(Conclusions)
• The 7/8 groups differed only for grades 3-4 acute GVHD
where HVG MM had less GVHD than the 7/8 bidirectional
MM (HR 0.52, p=0.0016) and GVH MM (HR 0.43,
p=0.0009) but not the 8/8 group (HR 0.83, p=0.39)
• There were no differences between the 7/8 groups for
relapse, chronic GVHD, neutrophil engraftment or graft
failure
• Unidirectional GVH vector mismatches have the same risk
as 7/8 bidirectional mismatches
• Recipients with a 7/8 HVG MM have a reduced risk of
acute GVHD without an increased risk of disease relapse
or graft failure compared to a 7/8 bi-directional MM at a
heterozygous locus
23. 23
Causes of Death
• The 7/8 bi-directional and GVH MM
groups had slightly higher deaths attributed
to GVHD, compared to the 8/8 and 7/8
HVG MM groups, 18.2% and 18.0% vs.
14.9% and 14.3%, respectively
• The 7/8 HVG MM group had more deaths
attributed to graft rejection than the 8/8, 7/8
GVH MM and 7/8 bidirectional groups,
9.5% vs. 0.6%, 1.1% and 1.6%, respectively
24. 24
Differences in the number of Mismatched Epitopes when the Patient
is Homozygous or Heterozygous at the Mismatched locus
25. 25
Homozygosity at a given locus vs
Heterozygosity
• Patients homozygous at a given locus when presenting
humoral sensitization tend to make anti-HLA antibodies
reactive with many (in some instances all but self antigens)
HLA antigens of the same locus
• Novel anti-HLA antibody screening techniques allow to
precisely identify anti-HLA antibodies defining unacceptable
or high risk mismatches. Therefore, donors can be excluded
or given lower priority on the basis of their HLA mismatch
and the patient’s antibody reactivity.
• Current conditioning/immunosupression (ATG) this risk for
primary graft loss mediated by T-cells may be greatly
reduced
26. 26
Homozygosity at a given locus vs
Heterozygosity
• Patients homozygous at a given locus when presenting
humoral sensitization tend to make anti-HLA antibodies
reactive with many (in some instances all but self antigens)
HLA antigens of the same locus
• Novel anti-HLA antibody screening techniques allow to
precisely identify anti-HLA antibodies defining unacceptable
or high risk mismatches. Therefore, donors can be excluded
or given lower priority on the basis of their HLA mismatch
and the patient’s antibody reactivity.
• Current conditioning/immunosupression (ATG) this risk for
primary graft loss mediated by T-cells may be greatly
reduced
27. DSA in TCD Haploidentical Stem Cell Transplantation
Ciurea SO, de Lima M, Cano P, Korbling M, Giralt S, Shpall EJ,
Wang X, Thall PF, Champlin RE, Fernandez-Vina M
DSA were detected in 5 of 24 consecutive patients
(21%)
4/24 patients had primary graft failure (PGF)
3/4 (75%) patients with DSA failed to engraft as
compared with 1/20 (5%) without DSA (P=0.008)
DSAEngraftment YES NO
YES 1 3
NO 19 1
“High risk of graft failure in patients with anti-HLA antibodies undergoing
haploidentical stem-cell transplantation”
Transplantation. 2009 Oct 27;88(8):1019-24
28. Recently published work: Anti-HLA
Antibodies and Virtual Cross Match in MUDs
Retrospective study - DSA found in 9/37 MUDT patients with
graft failure
1/78 had DSA in the matched control group of patients who
engrafted (TCR grafts, 85% mismatched at DP locus)
Spellman S, Bray R, Rosen-Bronson S, Haagenson M, Klein J,
Flesch S, Vierra-Green C, Anasetti C.
The detection of donor-directed, HLA-specific alloantibodies in
recipients of unrelated hematopoietic cell transplantation is
predictive of graft failure.
Blood. 2010 Apr 1;115(13):2704-8
PGF Control
DSA 9/37 (24%) 1/78 (1%)
Class I +/- Anti-DP 5 1
Anti-DP alone 4 0
DSA and PGF
RR = 24.8 – 28.1
29. Ciurea SO, Thall PF, Wang X, Wang SA, Hu Y, Cano P, Aung F, Rondon G,
Molldrem JJ, Korbling M, Shpall EJ, de Lima M, Champlin RE, Fernandez-Vina M.
Donor-specific anti-HLA Abs and graft failure in matched unrelated donor
hematopoietic stem cell transplantation.
Blood. 2011 Nov 24;118(22):5957-64
592 MUD TX
75 % of the 8/8 transplants present at least one
mismatch in DP, DQ, DRB3/4/5 in the HvG vector
20 % of HSC patients are immunized against HLA
HLA Immunization in FEMALE HSCT patients: 30%
HLA Immunization in MALE HSCT patients: 10%
3.3 % present antibodies against HLA-DP (1/2 MUD TX
have one or two DP mismatches and DSA anti HLA-DP)
30. Other Associations: Gender, Number of Pregnancies
and anti-HLA antibodies
Variable N
Coefficie
nt SE P-value OR 95% CI
Intercept -2.71 0.60 <0.0001 - -
Male vs. Females 0
pregnancies
356 0.73 0.62 0.24 2.1 0.62 - 6.94
Female: Number of
pregnancies = 1
(vs. 0)
37 1.85 0.70 0.008 6.3 1.62 -
24.85
Female: Number of
pregnancies ≥ 2
(vs. 0)
152 2.25 0.62 0.0003 9.5 2.83 -
32.02
Significant association between gender and the presence of
AHA: 30.8% females vs 12.1% males had anti-HLA
antibodies (p<0.0001)
7/8 pts with DSA were females
32. Anti-HLA antibodies in CBU
transplantation
DSA in Single Unit CBU TX
Double CBU and DSA:
• DSA against both Units
• DSA against one Unit
• No DSA
34. 34
“The impact of anti-HLA antibodies on unrelated cord blood
transplantations”
Takanashi M, Atsuta Y, Fujiwara K, Kodo H, Kai S, Sato H,
Kohsaki M, Azuma H, Tanaka H, Ogawa A, Nakajima K,
Kato S
Blood. 2010 Oct 14;116(15):2839-46
• 386 Single CBT; myeloablative, Median age 33
• HLA Immunization: 89 patients (23%); 20 cases with
DSA
• Neutrophil recovery @ day +60 :
• 83% for the ab-negative
• 73% for ab-positive/No-DSA
• 32% ab-positive/Yes-DSA
• Anti-HLA antibodies should be tested and considered
pre-transplantation in the selection of cord blood
36. 36
“Donor-specific anti-HLA antibodies predict outcome in double umbilical
cord blood transplantation”
Cutler C, Kim HT, Sun L, Sese D, Glotzbecker B, Armand P, Koreth J,
Ho V, Alyea E, Ballen K, Ritz J, Soiffer RJ, Milford E, Antin JH
Blood. 2011 Dec 15;118(25):6691-7
• 73 Double CBT; myeloablative (27%)or
RIC/ATG (73%); Median age 48
• 18 patients with DSA (11 Single Unit DSA,
7 DSA against both CBU)
41. DSA in the Study by Brunstein et al
• Lower cut-off for calling positve anti-HLA antibodies
• DSA against 1 Unit: n = 12; 2 graft failures
• DSA> 3000 MFI: n = 3; 1/3 had graft failure
• DSA against both Units: n= 6; 1 graft failure
• One had DSA> 3000 MFI : n = 4 ; 1/3 had graft failure
42. Impact of donor specific anti-HLA antibodies on graft
failure and survival after reduced intensity conditioning-
unrelated cord blood transplantation. A Eurocord,
Societe Francophone d'Histocompatibilite et
d'Immunogenetique (SFHI) and Societe Francaise de
Greffe de Moelle et de Therapie Cellulaire (SFGM-TC)
analysis
Boudifa A, Coeffic B, Devys A, De Matteis M, Dubois V,
Hanau D, Hau F, Jollet I, Masson D, Pédron B, Perrier P,
Picard C, Ramouneau-Pigot A, Volt F, Charron D, Gluckman
E, Loiseau P
Haematologica. 2012 Dec 14. [Epub ahead of print] PubMed
PMID: 23242594
43. 43
Anti-HLA antibodies in CBU
transplantation
• HvG vector, Serologic Level mismatches (class I)
• Sensitivity, specificity and quantitation of antibody detection are greatly
enhanced by novel solid phase assays
• Variations in end points and cut-off values
• Cross-match testing is not be practical in HSCT
• High risk of graft rejection in patients with D.S. Antibodies
• Higher mortality and morbidity associated to DSA
• Allo-antibodies directed against both class I and II HLA antigens
• Less mismatches in MUD than in CBU
• Anti-DP antibodies in MUD (mostly matched at other HLA loci)
• Anti-HLA antibody testing is warranted to all HSCT with known or presumed
HLA mismatches
• Further analysis for different graft sources and diseases is warranted
44. “Complement (C1q) fixing solid-phase screening for HLA antibodies
increases the availability of compatible platelet components for refractory
patients”
Fontaine MJ, Kuo J, Chen G, Galel SA, Miller E, Sequeira F, Viele M,
Goodnough LT, Tyan DB.
Transfusion. 2011 Dec;51(12):2611-8
• 13 highly sensitized refractory patients received 177 PLT units
incompatible by the IgG-SAB method
• The mean CPRA value was significantly lower by C1q-SAB (60%)
than by IgG-SAB (94%; p < 0.05)
• Patients showed significantly better corrected count increment with
C1q-compatible than with C1q-incompatible PLTs
• Results show that 75% of PLT units previously considered
incompatible were actually compatible
• For highly refractory patients to PLT transfusion, the C1q-based SAB
binding assay may be a better method for identifying clinically
relevant HLA antibodies and selecting PLT units that will result in
acceptable CCI
46. 46
Anti-HLA antibodies in CBU
transplantation
• Only 16-24 % PGF have DSA
• T-cell immunity
• Conditioning, Immunosuppressive regimens
(ATG, post TX Cyclophosphamide)
• Preservation of patient’s Immune System (Primary
Disease and Stage)
• Graft type and variations in HLA expression
• Graft Manipulation
47. 4747
Goals of Allogeneic BMT
• Absence of Graft versus Host Disease:
GvHD is mediated by donor’s T-cells
• Effective Immune reconstitution:
T-cells of donor origin may interact with patient’s tissues
and in some instances patient’s APCs
• Prevent Relapse:
GvL may be mediated by both, T-cells and NK cells of
donor origin; donor’s T cells causing GvHD may also
prevent relapse
• GvH: Major factor in Mortality and Morbidity: Once
engraftment is achieved; the mismatches in the GvH vector
play a major role in transplant outcome
48. Homozygosity at a given locus vs
Heterozygosity
• Patients homozygous at a given locus when presenting
humoral sensitization tend to make anti-HLA antibodies
reactive with many (in some instances all but self antigens)
HLA antigens of the same locus
• Novel anti-HLA antibody screening techniques allow to
precisely identify anti-HLA antibodies defining unacceptable
or high risk mismatches. Therefore, donors can be excluded
or given lower priority on the basis of their HLA mismatch
and the patient’s antibody reactivity.
• However, in light of current conditioning/immunosupression
(ATG) this risk for primary graft loss mediated by T-cells
may be greatly reduced
49. 49
Differences in the number of Mismatched Epitopes when the Patient
is Homozygous or Heterozygous at the Mismatched locus
56. Anti-HLA antibodies in CBU
transplantation
DSA in Single Unit CBU TX
Double CBU and DSA
DSA against both Units
DSA against one Unit
Even though the authors do not agree:
Higher mortality and morbidity associated to
DSA. Variations in end points and cut-off
values