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Prof. Narinder K Mehra  Dept of Transplant Immunology & Immunogenetics AIIMS, New Delhi  [email_address] Hematopoietic Ste...
Hematopoietic Stem Cell Transplantation <ul><li>1.  Hematologic Malignancies  </li></ul><ul><ul><li>Acute and Chronic Myel...
Bone Marrow Peripheral Blood Stem Cells (PBSC) Cord Blood Sources of Hematopoietic Stem Cells NKM / AIIMS
HSCT : FACTORS INFLUENCING SUCCESS  <ul><li>Original disease of the patient  </li></ul><ul><li>Prior  therapy  of the Pre-...
Chromosome 6  Gene map of the HLA region Class II Class III Class I 1.8 Mb 40 % of which have assumed immune functions  te...
Compatible Donor Search - Matching HLA Family- ¼ chance Unrelated –  1/500 - 0/10 million chance of match 70% patients do ...
Extraordinary polymorphism in HLA Number Class I Antigens Class I Alleles Class II Antigens Class II Alleles
Multiple DNA Based HLA Technologies SSP SSOP Reverse SSOP  SBT Luminex (Flow) DNA extraction (optimum quality, quantity, c...
DNA vs Serology: Example of a CML patient HLA Pt (P)/ Serology PCR based DNA typing Cousin Donor (CD) Low Resolution High ...
Why Is It Difficult to Find an HLA Identical Unrelated Donor ? <ul><li>Extensive allele & haplotype diversity </li></ul><u...
MHC Diversity :  Biological and clinical implications  Extreme MHC Diversity in India  Novel Alleles   - racial admixture ...
North Indians Diversity of HLA-A2 Caucasians Japanese Gambian Tissue Antigens  57, 502-507, 2001.  Hungarian Gypsies
Caucasoids Japanese  B*2705 B*2702 Blacks B*2705 B*2703 B*2705 B*2704 Thai B*2705 B*2704 B*2706 B*2707 Azores B*2705 B*270...
*  Multiple HLA-DR3 haplotypes Caucasians Indians A1-B8-DR3  (AH8.1) A26-B8-DR3 (AH8.2*)  Unique A24-B8-DR3 A2-B8-DR3 Chin...
What if an HLA-A,-B,-DR compatible sibling is not available in the family ? OPTIONS Extended family search Partially HLA c...
Antenatal HLA  &   Predictive Genetic Testing <ul><li>Thalassemias </li></ul><ul><li>Storage disorders </li></ul>ETHICS ? ...
HLA Matching   Siblings   Leukemias  Thal. M. Identical 177    42  Haploidentical 143    87  Unidentical   21    31  Donor...
Unrelated Donor Tx :    Thalassemia Major Pt: S W A26  A26 B8  B8 DR3  DR3 A26  A33 B8  B35 DR3 DRx AH A26  A11 B8  B35 DR...
How Can We Reduce Risk of  Allorecognition ? <ul><li>Select donor to resemble “self” </li></ul><ul><ul><li>HLA compatible ...
Balancing Act  – Strategy to Reduce One Complication May Increase Another T Cell Depletion Reduce GvHD Decrease engraftmen...
Bone  Marrow  Donors  Worldwide 13.8M Donors Jan, 2010 B.M.Donors =  13.8 M CBUs  = 176,779 75  Registries 37 CB Banks BMD...
History of Registries as Source of Unrelated HLA Compatible Donors <ul><li>Early on, unrelated donors through public drive...
311,311 277,081 62,841 1205 BMDW- Asian Component Total : 12.34M,  July,2008  95% 5% No of Donors
ASIAN   REGISTRIES Country Registry Year of Estb No of Donors MUD Tx JAPAN Japan Marrow Donor Program 1991  300,000 >8000 ...
Asian Indian Donor Marrow Registry (AIDMR) <ul><ul><ul><ul><ul><li>Needs and Requirements </li></ul></ul></ul></ul></ul><u...
<ul><li>Objectives   </li></ul><ul><li>Encourage  donor drive  through mass education programs </li></ul><ul><li>Recruit d...
AIDMR Targets <ul><ul><li>Atleast 50,000 donors representing various ethnicities </li></ul></ul><ul><ul><li>Special attent...
Donor Centres  AIDMR-National Network Transplant Centres AIIMS, SGPGI, IIH, CMC, PGI NBU, GSBTM AIIMS, N Delhi AHRR, N Del...
1.  Patient Diagnosis 2.  Family Screening for HLA Id sib- best option 3.  If not-available Family in distress 4.  Search ...
Probability of Finding Matched Donor for Next Patient <ul><li>Antigen level ABDR, ZKRD German Registry </li></ul><ul><li>M...
Ottinger et al, Blood 2003 MFD, early disease MUD, early disease ISD, early disease ISD, advanced disease MUD, advanced di...
Risk of acGvHD after HSCT from ISDs, MFDs and MUDs MFD MUD ISD Ottinger et al, Blood 2003
MFD ,  MM2 MFD ,  MM1 MUD ISD MFD ,  MMO Impact of mismatched HLA Loci on the risk of Ac GvHD Days after Transplantation p...
 
Probability of survival after  Allogeneic Stem Cell Transplant Hows et al, BMT 2006
<ul><li>Umbilical Cord Blood (UCB) </li></ul><ul><ul><li>Benefits and Drawbacks </li></ul></ul><ul><ul><li>Private and Pub...
<ul><li>HLA Compatible hES cell Lines </li></ul><ul><li>Promising Source of Transplantation to replace diseased or damaged...
<ul><li>Important study that provides basis for Stem Cell Banking </li></ul><ul><li>A bank of 150 hESCs could provide a fu...
Creation of HLA Specific Somatic Cells by  SCNT Technology: Indian effort <ul><li>Skin Biopsies from 2 males homozygous fo...
Source of Somatic Cells Collborative study between AIIMS and NIRRH Fetal fibroblasts Human fetal fibroblasts already being...
 
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Summary <ul><li>Novel approaches to HCT are improving outcomes and applicability of HCT </li></ul><ul><li>HCT should be di...
AIIMS – TII GROUP
Derivation and Characterization of two genetically unique huESC lines on in-house derived human feeders  (Stem cells and d...
 
Project with a Strong Basic Research Component  as well as a Future Translational Goal in the Area of Stem Cell Research E...
Creating HLA Homozygous ES Cell Lines <ul><li>If a particular HLA haplotype is prevalent, the derived cell line will have ...
Survival among HLA-A,B and DRB1 allele matched pairs by number of mismatched class I loci Years after Transplant 1 Mismatc...
<ul><li>Molecular matching is critical for unrelated HSCT program </li></ul><ul><li>Allele level matching is associated wi...
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Hematopoietic Stem Cell Transplantation : Opportunities and challenges

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By Prof. N. K. Mehra

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Hematopoietic Stem Cell Transplantation : Opportunities and challenges

  1. 1. Prof. Narinder K Mehra Dept of Transplant Immunology & Immunogenetics AIIMS, New Delhi [email_address] Hematopoietic Stem Cell Transplantation : Opportunities and challenges
  2. 2. Hematopoietic Stem Cell Transplantation <ul><li>1. Hematologic Malignancies </li></ul><ul><ul><li>Acute and Chronic Myeloid Leukemia </li></ul></ul><ul><ul><li>Acute and Chronic lymphocytic leukemia </li></ul></ul><ul><ul><li>Myeloddysplastic Syndrome </li></ul></ul><ul><ul><li>Lymphomas – Hadgkins and Non Hodgkins </li></ul></ul><ul><ul><li>Multiple Myelomas </li></ul></ul><ul><li>2. Non Malignant Disorders </li></ul><ul><ul><li>Severe Aplastic Anemias (SAA) </li></ul></ul><ul><ul><li>Hurler’s Syndrome </li></ul></ul><ul><ul><li>Wiskott – Aldrich Syndrome </li></ul></ul><ul><ul><li>Diamond – Blackfan Anemia </li></ul></ul><ul><ul><li>Osteopetrosis </li></ul></ul><ul><li>3. Inherited Blood Disorders </li></ul><ul><ul><li>Beta Thalassaemia Major </li></ul></ul><ul><li>4. Severe combined immunodeficiency (SCID) </li></ul><ul><li>5. Pathologic States including autoimmune diseases </li></ul><ul><li>6. Solid Tumors (Breast cancer, Teratomas, ovarian tumors etc.) </li></ul>
  3. 3. Bone Marrow Peripheral Blood Stem Cells (PBSC) Cord Blood Sources of Hematopoietic Stem Cells NKM / AIIMS
  4. 4. HSCT : FACTORS INFLUENCING SUCCESS <ul><li>Original disease of the patient </li></ul><ul><li>Prior therapy of the Pre-Tx conditioning regimen </li></ul><ul><li>Genetic disparity between donor and recipient </li></ul><ul><li>No. of hematopoietic stem cells transfused </li></ul><ul><li>Presence / absence of donor T cells </li></ul><ul><li>Post transplant immune suppression therapy </li></ul>NKM / AIIMS
  5. 5. Chromosome 6 Gene map of the HLA region Class II Class III Class I 1.8 Mb 40 % of which have assumed immune functions tel. Long arm cen. short arm tel. 6p 21.3 HLA region Bf DP DM DQ DR C4 C2Hsp70TNF B C E A G F 128 functional genes Most polymorphic Ag presentation, crucial in organ and HSCT
  6. 6. Compatible Donor Search - Matching HLA Family- ¼ chance Unrelated – 1/500 - 0/10 million chance of match 70% patients do not have family donor
  7. 7. Extraordinary polymorphism in HLA Number Class I Antigens Class I Alleles Class II Antigens Class II Alleles
  8. 8. Multiple DNA Based HLA Technologies SSP SSOP Reverse SSOP SBT Luminex (Flow) DNA extraction (optimum quality, quantity, contamination free) is critical
  9. 9. DNA vs Serology: Example of a CML patient HLA Pt (P)/ Serology PCR based DNA typing Cousin Donor (CD) Low Resolution High Resolution A P 34, 2 3401, 02 3401, 0207 CD 34, 2 3402, 02 3402, 0211 B P 8, 40 0802, 4003 0802, 4003 CD 8, 40 0801, 4007 0801, 4007 Cw P 4, - 07, 04 0704, 04 CD 4, 7 07 , 0501 07(01-03), 0501 DR P 4, 2 15, 04 1501, 0405 CD 4, 2 15, 04 1502, 0404 DQB1 P 3, 1 03, 01 0301, 0601 CD 3, 1 03, 01 0302, 0602 Match Full Partial Major Grade Match Mismatch Mismatches NKM / AIIMS
  10. 10. Why Is It Difficult to Find an HLA Identical Unrelated Donor ? <ul><li>Extensive allele & haplotype diversity </li></ul><ul><li>Differences among human populations </li></ul><ul><ul><li>Allele & haplotype frequencies </li></ul></ul><ul><ul><li>Novel & unique issues </li></ul></ul>
  11. 11. MHC Diversity : Biological and clinical implications Extreme MHC Diversity in India Novel Alleles - racial admixture <ul><li>Founder effect </li></ul><ul><li>Selective environmental </li></ul><ul><li>& microbial pressure </li></ul>Oriental influence Unique HLA haplotypes - disease associated Unique repertoire of peptide presenting molecules
  12. 12. North Indians Diversity of HLA-A2 Caucasians Japanese Gambian Tissue Antigens 57, 502-507, 2001. Hungarian Gypsies
  13. 13. Caucasoids Japanese B*2705 B*2702 Blacks B*2705 B*2703 B*2705 B*2704 Thai B*2705 B*2704 B*2706 B*2707 Azores B*2705 B*2702 B*2703 B*2708 B*2707 AIIMS / NKM Asian Indians B*2707 ( 11% ) B*2704 ( 29% ) B*2702 ( 1.6%) B*2714 ( 0.01% ) B*2705 (57% )
  14. 14. * Multiple HLA-DR3 haplotypes Caucasians Indians A1-B8-DR3 (AH8.1) A26-B8-DR3 (AH8.2*) Unique A24-B8-DR3 A2-B8-DR3 Chinese Indians A33-B58-DR3 (AH58.1) A33-B58-DR3 Indians ???? A2-B50-DR3 Unique *Witt , Mehra, Kaur,….et al Tissue Antigens 2002
  15. 15. What if an HLA-A,-B,-DR compatible sibling is not available in the family ? OPTIONS Extended family search Partially HLA compatible donors Ante Natal HLA typing Unrelated Donors through registry NKM / AIIMS
  16. 16. Antenatal HLA & Predictive Genetic Testing <ul><li>Thalassemias </li></ul><ul><li>Storage disorders </li></ul>ETHICS ? MORAL ISSUES ? PSYCHOLOGY ? ?
  17. 17. HLA Matching Siblings Leukemias Thal. M. Identical 177 42 Haploidentical 143 87 Unidentical 21 31 Donor Selection : AIIMS Experience (1998 – Feb 2003) NKM / AIIMS * CVS typing reconfirmed after birth in 3 cases * Out of these, two were transplanted CVS* N+ = 33 14 (42.4%) 12 (36.4%) 7 (21.2%)
  18. 18. Unrelated Donor Tx : Thalassemia Major Pt: S W A26 A26 B8 B8 DR3 DR3 A26 A33 B8 B35 DR3 DRx AH A26 A11 B8 B35 DR3 DR15 A26 A11 B8 B35 DR3 DR15 AH I Pt: S Ch A26 A11 B8 B8 DR3 DR3 AH AH A1 A11 B52 B8 DR3 DR3 A26 A26 B8 B8 DR3 DR3 II Ancestral Haplotypes Conserved in the race ?
  19. 19. How Can We Reduce Risk of Allorecognition ? <ul><li>Select donor to resemble “self” </li></ul><ul><ul><li>HLA compatible sib or 10/10 match </li></ul></ul><ul><li>Remove mature immune cells from graft </li></ul><ul><ul><li>T cell depletion </li></ul></ul><ul><ul><li>Umbilical cord blood as source HSC </li></ul></ul><ul><li>Reduce “danger” signals </li></ul><ul><ul><li>Reduced conditioning regimen </li></ul></ul><ul><li>Inactivate alloreactive cells in transplanted recipient </li></ul><ul><ul><li>Immune suppressive drugs- cyclosporine, methotrexate, corticosteroids, anti-thymocyte globulin </li></ul></ul>
  20. 20. Balancing Act – Strategy to Reduce One Complication May Increase Another T Cell Depletion Reduce GvHD Decrease engraftment Increase infection Increase risk relapse
  21. 21. Bone Marrow Donors Worldwide 13.8M Donors Jan, 2010 B.M.Donors = 13.8 M CBUs = 176,779 75 Registries 37 CB Banks BMDW France Greffe de Moelle 125,843 Austrian Bone Marrow Donors 52,029 National Marrow Donor Program 3,927,577 Anthony Nolan Research Center 358,285 Australian Bone Marrow Donor Registry 162,450 German Registry of Bone Marrow Donors 2,299,322 Asian Indian Donor Marrow Registry 3,630 1994
  22. 22. History of Registries as Source of Unrelated HLA Compatible Donors <ul><li>Early on, unrelated donors through public drives by families & from HLA-typed platelet donor panels </li></ul><ul><li>1974 patient’s mother founds Anthony Nolan Bone Marrow Register </li></ul><ul><li>1988 World Marrow Donor Association </li></ul><ul><li>1988 Bone Marrow Donors Worldwide </li></ul><ul><li>Today, 58 registries in 43 countries; 38 cord blood banks in 21 countries with >10 million volunteer donors </li></ul><ul><li>>1/3 donors come from countries different than patient </li></ul><ul><li>Patient of Indian origin has 1/10 th chance of finding a donor </li></ul>
  23. 23. 311,311 277,081 62,841 1205 BMDW- Asian Component Total : 12.34M, July,2008 95% 5% No of Donors
  24. 24. ASIAN REGISTRIES Country Registry Year of Estb No of Donors MUD Tx JAPAN Japan Marrow Donor Program 1991 300,000 >8000 CHINA Chinese Marrow Donor Program 1992 950,000 >1117 SINGAPORE Bone Marrow Donor Program 1993 44,000 >215 TAIWAN Budhist Tzu Chi Marrow Donor Registry 1993 319,000 >1800 KOREA Korea Marrow Donor Program 1994 144,970 >1477 THAILAND Thai Stem Cell Donor Registry
  25. 25. Asian Indian Donor Marrow Registry (AIDMR) <ul><ul><ul><ul><ul><li>Needs and Requirements </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Genetic Diversity of HLA </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Novel Alleles, Unique Haplotypes </li></ul></ul></ul></ul></ul>Established in AIIMS in 1994 as a National level Registry
  26. 26. <ul><li>Objectives </li></ul><ul><li>Encourage donor drive through mass education programs </li></ul><ul><li>Recruit donors with ‘novel alleles’ and ‘unique haplotypes’ from different ethnicities </li></ul><ul><li>Regional efforts </li></ul><ul><li>Develop and adopt good matching algorithms </li></ul><ul><li>Keep updating HLA typing technologies </li></ul><ul><li>Encourage and support research that will reduce the need of HLA matching requirements </li></ul>Asian Indian Donor Marrow Registry (AIDMR)
  27. 27. AIDMR Targets <ul><ul><li>Atleast 50,000 donors representing various ethnicities </li></ul></ul><ul><ul><li>Special attention to donors with novel HLA alleles and unique haplotypes </li></ul></ul><ul><ul><li>Donor retention issues: involvement of volunteers/ family members/ social scientists </li></ul></ul><ul><ul><li>Technology development and updates including QC issues </li></ul></ul><ul><ul><li>In-house creation of HLA typing kits/ reagents </li></ul></ul><ul><ul><li>Financial issues: Test cost, BMT cost </li></ul></ul><ul><ul><li>BMDW participation: marrow exchange </li></ul></ul><ul><ul><li>International collaboration </li></ul></ul>
  28. 28. Donor Centres AIDMR-National Network Transplant Centres AIIMS, SGPGI, IIH, CMC, PGI NBU, GSBTM AIIMS, N Delhi AHRR, N Delhi CMC, Vellore TMH, Mumbai SGPGI, Lucknow Apollo, Chennai PGI, Chd KEM, Mumbai
  29. 29. 1. Patient Diagnosis 2. Family Screening for HLA Id sib- best option 3. If not-available Family in distress 4. Search for options : a) extended family search: not always rewarding except in consanginous marriages b) Prenatal genetic testing & HLA analysis- useful in disease like thalassemia major unrelated HSCT c) Search in national registry- donor pool too small d) Search in international registry: BMDW, WMDA, ANT etc STEPS INVOLVED IN MUD TRANSPLANTATION
  30. 30. Probability of Finding Matched Donor for Next Patient <ul><li>Antigen level ABDR, ZKRD German Registry </li></ul><ul><li>More volunteers, more likely to find a match </li></ul>Mueller et al, Human Immunol 64:137, 2003 Registry Size
  31. 31. Ottinger et al, Blood 2003 MFD, early disease MUD, early disease ISD, early disease ISD, advanced disease MUD, advanced disease MFD, advanced disease Overall Survival after allo HSCT from ISDs, MFDs and MUDs Years after Transplantation
  32. 32. Risk of acGvHD after HSCT from ISDs, MFDs and MUDs MFD MUD ISD Ottinger et al, Blood 2003
  33. 33. MFD , MM2 MFD , MM1 MUD ISD MFD , MMO Impact of mismatched HLA Loci on the risk of Ac GvHD Days after Transplantation p Ottinger et al, Blood 2003
  34. 35. Probability of survival after Allogeneic Stem Cell Transplant Hows et al, BMT 2006
  35. 36. <ul><li>Umbilical Cord Blood (UCB) </li></ul><ul><ul><li>Benefits and Drawbacks </li></ul></ul><ul><ul><li>Private and Public Cord Blood Banks </li></ul></ul><ul><ul><li>Affordability issues </li></ul></ul><ul><ul><li>Controversaries </li></ul></ul><ul><li>Creation of HLA Compatible Stem Cell Banks </li></ul><ul><ul><li>Human Embryonal Stem Cell lines (hESc) </li></ul></ul><ul><ul><li>150 lines covering most HLA types </li></ul></ul><ul><ul><li>Homozygous HLA haplotype lines </li></ul></ul><ul><ul><ul><ul><ul><li>Even 10 lines may be sufficient for a given population, covering common haplotypes </li></ul></ul></ul></ul></ul>Alternate Sources
  36. 37. <ul><li>HLA Compatible hES cell Lines </li></ul><ul><li>Promising Source of Transplantation to replace diseased or damaged tissue (Neurodegenerative , CVD, DM). </li></ul><ul><li>Can be propagated indefinitely in an undifferentiated state while retaining pluripotency </li></ul><ul><li>Differentiated progeny express HLAs leading to graft rejection; matching strategies required </li></ul><ul><li>Effective strategies need to be developed e.g. i) bank of HLA typed hES cells ii) Creation of HLA homozygous cell lines (allelic, haplotypic) </li></ul>
  37. 38. <ul><li>Important study that provides basis for Stem Cell Banking </li></ul><ul><li>A bank of 150 hESCs could provide a full match(A,B,DR) for ~ 20%, or a beneficial match (1MM) for a large majority </li></ul><ul><li>A panel of 10 highly selected homozygous donors could provide the max benefit for HLA matching </li></ul><ul><li>No line homozygous for all HLA loci has yet been derived </li></ul><ul><li>Population based HLA phenotype data necessary </li></ul>Banking of Human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching Craig Taylor et al Lancet 366:2019-25, 2005
  38. 39. Creation of HLA Specific Somatic Cells by SCNT Technology: Indian effort <ul><li>Skin Biopsies from 2 males homozygous for HLA haplotype AH 8.2, which is ‘unique’ to the Indian population </li></ul><ul><li>3.03% of healthy Indians and >25% of those with Type 1 Diabetes and celiac disease possess this haplotype (Dr Mehra’s group, AIIMS) </li></ul><ul><li>Banking of such known and common HLA haplotypes could benefit several patients requiring HSCT </li></ul><ul><li>Making an ES cell line by SCNT is possible, but challenging. Recent success with iPS technology (Shinya Yamanaka’s group) provides further hope and ecouragement. </li></ul>
  39. 40. Source of Somatic Cells Collborative study between AIIMS and NIRRH Fetal fibroblasts Human fetal fibroblasts already being successfully grown at the NIRRH by Dr Deepa Bhartiya Aneuploid cases from a Cytogenetics lab (n= 10) Adult fibroblasts Selection of HLA Homozygous individuals positive for Ancestral Haplotype , AH8.2 by the AIIMS Group of Prof N.K. Mehra Adult skin biopsies, Cytogenetics lab (n=2)
  40. 42. cc
  41. 43. cc
  42. 44. Summary <ul><li>Novel approaches to HCT are improving outcomes and applicability of HCT </li></ul><ul><li>HCT should be discussed early in the course of the disease </li></ul><ul><li>A team approach involving the Hematologist/Geneticist, Immunologist, Transplanter and Family/Patient advocate is essential </li></ul>
  43. 45. AIIMS – TII GROUP
  44. 46. Derivation and Characterization of two genetically unique huESC lines on in-house derived human feeders (Stem cells and development 2008)
  45. 48. Project with a Strong Basic Research Component as well as a Future Translational Goal in the Area of Stem Cell Research Establishing the Technology to Derive Human Embryonic Stem Cell Lines by Somatic Cell Nuclear Transfer and Parthenogenesis NIRRH, Mumbai - Deepa Bhartiya and group AIIMS, New Delhi – Narinder Mehra, Gurvinder Kaur Other collaboators…….
  46. 49. Creating HLA Homozygous ES Cell Lines <ul><li>If a particular HLA haplotype is prevalent, the derived cell line will have potential to treat several individuals </li></ul><ul><li>Idea is to bank most common haplotype ES cell lines so that most of patients can benefit with relatively smaller cohort of cell lines </li></ul><ul><li>Available literature suggests that such HLA homozygous cell lines could be derived by Parthenogenesis </li></ul><ul><li>pES cell lines are pluripotent and have no greater safety risks compared to conventional hES cell lines. </li></ul><ul><li>Such cell lines with uniparental disomy have unique advantage during transplantation since they are homozygous and can be transplanted into both homozygous and heterozygous recipients without rejection </li></ul>
  47. 50. Survival among HLA-A,B and DRB1 allele matched pairs by number of mismatched class I loci Years after Transplant 1 Mismatch (n=317) 0 Mismatches (n=791) 2 Mismatches (n=117) Flomenberg et al, Blood 2004
  48. 51. <ul><li>Molecular matching is critical for unrelated HSCT program </li></ul><ul><li>Allele level matching is associated with lower risks of graft failure, GVHD and transplant related mortality (TRM) </li></ul><ul><li>Clinical effects of multilocus mismatching are additive : Quantitative effects </li></ul><ul><li>Sequence matching to define ‘residues’ that are well tolerated without GVHD and TRM: Qualitative effects </li></ul>Unrelated HSCT: lessons HLA Matching Strategies NKM / AIIMS

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