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Transplantation

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Transplantation

Presented by Sirapassorn Sornphiphatphong, MD.

2015

Published in: Health & Medicine
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Transplantation

  1. 1. Transplantation Reviewed by Sirapassorn Sornphiphatphong, M.D.
  2. 2. Overview • Definition in transplantation • Adaptive immune responses to allografts • Graft rejection • Hematopoietic Stem Cell Transplantation
  3. 3. Overview of Hematopoietic Stem Cell Transplantation • Sources of HSCT • Donor selection and manipulation of the graft • Complications of HSCT – Graft rejection – Graft-versus-host disease • HSCT for The Treatment of Primary Immunodeficiency Disorders
  4. 4. Transplantation • Treatment for replacement of non-functioning organs and tissues with healthy organs or tissues • Increasing during the past 45 years • Hematopoietic stem cells, kidneys, livers, and hearts Abbas AK, et al. Cellular and molecular immunology Ed 8th
  5. 5. Transplantation • Graft: cells, tissues, or organs • Donor: provides the graft • Recipient, host: who receives the graft • Orthotopic transplantation; normal anatomic location • Heterotopic transplantation: different site Abbas AK, et al. Cellular and molecular immunology Ed 8th
  6. 6. Transplantation • Autologous graft: to the same individual • Syngeneic graft: two genetically identical individuals • Allogeneic graft, allograft: between two genetically different individuals of the same species • Xenogeneic graft , xenograft: different species Abbas AK, et al. Cellular and molecular immunology Ed 8th
  7. 7. Adaptive immune responses to Allografts • Ag that stimulate adaptive immune responses against allografts are histocompatibility proteins • Strong rejection reactions; major histocompatibility complex (MHC) molecules • Weak or slower rejection reactions; minor histocompatibility antigens Abbas AK, et al. Cellular and molecular immunology Ed 8th
  8. 8. Adaptive immune responses to Allografts • Allogeneic MHC molecules of a graft can be presented for recognition by the recipient’s T cells in 2 different ways; the direct and indirect pathways • Direct allorecognition can generate both CD4+ and CD8+ T cells that recognize graft antigens and contribute to rejection Abbas AK, et al. Cellular and molecular immunology Ed 8th
  9. 9. Abbas AK, et al. Cellular and molecular immunology Ed 8th
  10. 10. Abbas AK, et al. Cellular and molecular immunology Ed 8th
  11. 11. Abbas AK, et al. Cellular and molecular immunology Ed 8th
  12. 12. Graft rejection • Classified on the basis of histopathologic features and the time course of rejection after transplantation Abbas AK, et al. Cellular and molecular immunology Ed 8th Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  13. 13. Hyperacute Rejection • Thrombotic occlusion of the graft vasculature • Within minutes to hours after host blood vessels are anastomosed to graft vessels • Mediated by preexisting antibodies in the host circulation that bind to donor endothelial antigens
  14. 14. Acute Rejection • Injury to the graft parenchyma and blood vessels mediated by alloreactive T cells and antibodies • Several days to a few weeks • Immunosuppression Abbas AK, et al. Cellular and molecular immunology Ed 8th
  15. 15. Chronic Rejection and Graft Vasculopathy • In the kidney and heart: vascular occlusion and interstitial fibrosis • Lung transplants: thickened small airways (called bronchiolitis obliterans) • Liver transplants: fibrotic and non-functional bile ducts Abbas AK, et al. Cellular and molecular immunology Ed 8th
  16. 16. Prevention and Treatment of Allograft Rejection • Minimize alloantigenic differences between the donor and recipient • ABO blood typing: avoid hyperacute rejection • HLA alleles – HLA-A, HLA-B, and HLA-DR – Zero-antigen mismatches predict the best survival Abbas AK, et al. Cellular and molecular immunology Ed 8th
  17. 17. Hematopoietic Stem Cell Transplantation
  18. 18. Hematopoietic Stem Cell Transplantation • HLA discovery in 1968 • Human stem cell transplantation (HSCT) provide treatment for a variety of congenital and acquired disorders; SCID in 1968 Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  19. 19. Sources of hematopoietic stem cells for transplantation Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  20. 20. Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  21. 21. Bone marrow stem cells • Multiple aspirations along the iliac crests under general anesthesia • 500 mL- 1 L depended on the type of transplant and on the weight of the recipient • HLA-identical transplantation – injected intravenously without further manipulation into a central line in the recipient • Mismatched transplantation – T-cell depleted and injected intravenously Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  22. 22. Peripheral blood stem cells • G-CSF to the donor, 10 μg/kg/day x 5 days • Purified by positive selection, enumerated and injected Cord blood • Collected in heparinized medium and stored in liquid nitrogen, and small aliquots are preserved for HLA typing • Thawed and injected into the recipient without further manipulation Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  23. 23. Donor selection and manipulation of the graft
  24. 24. HSCT from a related HLA-identical donor • Best for rapid engraftment and immune reconstitution • The mature T cells contained in the graft provide a first line of immune reconstitution after transplant • Rapid increase circulating T lymphocytes 2 weeks after HSCT Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  25. 25. HSCT from a haploidentical donor • No such donor is available • based on the ability of donor-derived stem cells to repopulate the recipient’s vestigial thymus and give rise to fully mature T lymphocytes • life-saving procedure of SCID infants Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  26. 26. T-cell depletion • Soybean lectin: agglutination of mature marrow cells and removed by sedimentation • E-rosetting (with sheep erythrocytes) and density gradient centrifugation • Incubation of the marrow with monoclonal antibodies to T lymphocytes plus complement; Campath-1G, Leu 1 • Positive selection of CD34+ cells using monoclonal antibody affinity Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  27. 27. HSCT from matched unrelated donors • Increasingly used to treat severe primary immunodeficiencies • Bone Marrow Donors Worldwide (BMDW) registry • 3–4 months to identify a MUD • Preparative chemotherapy regimen in the recipient (even in the case of SCID) and graft versus-host prophylaxis Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  28. 28. HSCT using unmanipulated cord blood • Lower risk of GvHD than with MUD • Based on the urgency of the transplant, the cell dose required, and the number of HLA disparities • Requires pre-transplant conditioning and GvHD prophylaxis, irrespective of the underlying disease Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  29. 29. Sources of hematopoietic stem cells for transplantation Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  30. 30. Complications of hematopoietic stem cell transplantation • Conditioning regimen toxicity – affect several organs e.g. busulfan-lung damage, veno-occlusive disease – anemia, thrombocytopenia, and leukopenia • Graft rejection • Graft-versus-host disease • Infections Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  31. 31. Graft rejection • Immunocompetent cells in the host specifically recognize and react to donor- derived stem cells – the degree of immunocompetence of the host – the degree of HLA disparity – the number of stem cells infused – the type of conditioning regimen used – the possible pre-sensitization of the host to donor histocompatibility antigens Abbas AK, et al. Cellular and molecular immunology Ed 8th Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  32. 32. Graft rejection • SCID, graft rejection unlikely because of the profound immunodeficiency • Regimen: busulfan + cyclophosphamide, ± antithymocyte globulin (ATG) • Phagocytic or hemophagocytic cell disorders, a more aggressive conditioning regimen Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  33. 33. Acute graft-versus-host disease • Donor-derived T lymphocytes to the recipient’s antigens • Early as 1 week after HSCT • Potentially fatal • The major risk factors for aGvHD include – HLA mismatch – Older age of the recipient – Gender mismatch – Prior herpes virus infection Abbas AK, et al. Cellular and molecular immunology Ed 8th Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  34. 34. Acute GvHD • Highgrade fever, MP rash (confluent), exfoliative dermatitis, diarrhea, and liver abnormalities (hepatomegaly, ↑elevated liver enzymes, jaundice), protein-losing enteropathy, abdominal pain • Third space loss • Bone marrow aplasia, high susceptibility to infections Abbas AK, et al. Cellular and molecular immunology Ed 8th Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  35. 35. Chronic GvHD • Symptoms persist or appear after 100 days • Skin changes (scleroderma-like lesions, hyperpigmentation, hyperkeratosis, skin atrophy, ulcerations), tissue fibrosis, limitation of joint motility • Fibrosis of exocrine glands (sicca syndrome), fibrosis of lungs and liver, immune dysregulation and autoimmunity Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  36. 36. Chronic GvHD • Acute GvHD represents a major risk factor for cGvHD • Older age of the recipient • Transplantation from a multiparous female donor into a male recipient • Minor histocompatibility incompatibility Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  37. 37. Prevention of GvHD • Fully matched donor • T-cell depleted HLA-mismatched donor • Pharmacological GvHD prophylaxis – Cyclosporine A daily for 6 months, or methotrexate (15 mg/m2 on the first day, and then 10 mg/m2 at day 3, 6 – or combination – ATG Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  38. 38. Treatment of GvHD • Immunosuppressive drugs • Steroids, ATG, mycophenolate mofetil, cyclosporine A, monoclonal antibodies directed to HLA (anti-CD3) or to Th1-type cytokines (anti- TNF-α) and cytokine receptors (anti-CD25, daclizumab) • Topical steroids and calcineurin inhibitors may alleviate mucosal and skin symptoms • Ursodeoxycholic acid may be useful in cGvHD with significant liver involvement Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  39. 39. Infections • Adenovirus, CMV, EBV, parainfluenzae III virus. PCP, aspergillus, bacterial infection • Viral infection after HSCT may cause interstitial pneumonia, enteritis, and encephalitis • EBV cause B-cell lymphoproliferative disease (BLPD) Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  40. 40. HSCT for The Treatment of Primary Immunodeficiency Disorders
  41. 41. HSCT for SCID • Immune suppression is not required • No conditioning regimen is necessary in related HLA-identical donor • US centers adopt same policy for T cell-depleted mismatched HSCT • European centers tend to use conditioning regimens prior to mismatched or MUD HSCT, particularly in SCID with residual autologous NK
  42. 42. Survival following HSCT for SCID • Related HLA-identical, MUD, and T cell-depleted haploidentical HSCT were 100%, 94%, and 52%, respectively • Has improved over the years Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  43. 43. Factors influence survival • Younger age at transplantation leads to superior survival – Among 38 infants who were treated by Buckley and collaborators before 3.5 months of age, 37 (97%) have survived • Co-trimoxazole prophylaxis for recipients • Absence of pre-transplant pulmonary infection among recipients • Type of SCID Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  44. 44. Factors influence survival • Survival following related HLA-mismatched HSCT is better in infants with B+ SCID than with B− SCID (64% vs 36%, respectively) • The poorer outcome in infants with B− SCID may reflect the presence of autologous NK cells detectable in most of these infants Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  45. 45. Complications following HSCT for SCID • 56% of all deaths were due to infections, 25% to GvHD, and 5% to BLPD (B-cell lymphoproliferative disease) • Immune dysregulation and autoimmunity Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  46. 46. Quality and kinetics of T-cell immune reconstitution • The effectiveness of HSCT in SCID: the normalization of the number and function of T lymphocytes • Reconstitution differs substantially depending on the type of transplantation • The kinetics of T-cell reconstitution influenced by the recipient’s age • Early transplantation (<3.5 months of age) leads to superior thymic output Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  47. 47. Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  48. 48. Quality and kinetics of T-cell immune reconstitution Related HLA-identical donor • The unmanipulated graft contains mature T lymphocytes • expanded in 2 weeks • Oligoclonal, have a memory (CD45R0) phenotype • Fully competent, and provide the recipient with functional immunity MUD • Present mature T cells • Conditioning regimen partly impairs immune development • Naive (CD45RA+ CD31+) T lymphocytes appear in 3–4 months • Number tends to peak 1 year after HSCT Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  49. 49. Quality and kinetics of T-cell immune reconstitution Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  50. 50. • T-cell receptor excision circles (TRECs); extrachromosomal DNA episomes generated during V(D)J recombination • not duplicated during mitosis • identify newly generated naive T lymphocytes Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  51. 51. Quality and kinetics of T-cell immune reconstitution • Quantification of TRECs • assess engraftment of bona fide stem cells and to monitor the persistence of immunity • Decline by 10 years • Possible that the SCID thymus is not able to sustain active thymopoiesis for as long as a normal thymus Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  52. 52. Reconstitution of B- and NK-cell immunity • ≥2 years to develop the engraftment of B cells for SCID • 6 of12 recipients of HLA-identical bone marrow, and 21 of 76 patients treated by unconditioned T cell-depleted haploidentical transplant had evidence of donor-derived B lymphocytes • 62 of 102 survivors were requiring intravenous immunoglobulins Buckley RH. Annu Rev Immunol 2004
  53. 53. Reconstitution of B- and NK-cell immunity • Depend on the nature of the genetic defect • B+ SCID, IL7RA gene defect usually develop normal B-cell immunity after HSCT even if no donor-derived B cells are present • γc or JAK3 deficiency (both of which compromise B-cell function) often remain dependent on immunoglobulin substitution • More limited data are available about reconstitution of NK cell function Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  54. 54. HSCT for immunodeficiencies other than SCID
  55. 55. HSCT for immunodeficiencies other than SCID • Residual T cell-mediated immunity • pre-transplant conditioning regimen is required, even HLA-identical donor • Alternative donors (MUDs and cord blood) • Medical emergency • Clinical history and quality of life Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  56. 56. Survival following HSCT • 23/79 HLA-identical transplant • 13/79 by T cell-depleted haploidentical HSCT • 43/79 by MUD HSCT • The survival rates: 78.5%, 53.8%, 78.1% Rich RR, et al. Clinical Immunology principles and practice. Ed 3rd
  57. 57. HSCT for immunodeficiencies other than SCID HLA-identical Haploidentical MUD Omenn’s syn 75% 41% 50% MHC class II def 54% 32% - WAS 87% 52% 71% FHL 71% - 70% Cartilage-hair hypoplasia Over all 50% Purine nucleoside phophorylate Overall 50% CD40L def Overall 46% at 25 yr of age
  58. 58. Wiskott–Aldrich syndrome • Early as 1968, with partial success • Full correction following HSCT first in 1978 • Good outcome in HLA-identical HSCT • MUD HSCT was effective especially <5 years • Cord blood transplantation increasingly
  59. 59. Cytotoxicity defects • Familial hemophagocytic lymphohistiocytosis (FHL) – a stable donor chimerism ≥20% is sufficient to provide long-term remission – genetic testing is strongly recommended before HSCT from a sibling is attempted • Chediak–Higashi syndrome – Better results with HSCT from HLA-identical siblings or MUDs – 3 patients, all are alive and in full remission
  60. 60. HSCT for immunodeficiencies other than SCID • Poor outcome in Interferon-Ƴ receptor 1 deficiency, IPEX syndrome (Immunodysregulation, polyendocrinopathy, enteropathy, X- linked)

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