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Limitations to the Field of Transplantation

Limitations to the Field of Transplantation. Drug treatment-related complications Chronic rejection Availability of organs. TOLERANCE. Specific unresponsiveness to the donor of the recipient’s immune system. The donor is regarded as “self”.

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Limitations to the Field of Transplantation

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  1. Limitations to the Field of Transplantation • Drug treatment-related complications • Chronic rejection • Availability of organs

  2. TOLERANCE • Specific unresponsiveness to the donor of the recipient’s immune system. • The donor is regarded as “self”. • Therefore, no immunosuppressive drugs are needed to prevent rejection

  3. Bone Marrow Induces Tolerance • Animal studies >25 years ago showed that mixed bone marrow chimerism educates the immune system to make it tolerant of the donor • We have aimed at making this approach less toxic and therefore clinically applicable

  4. Bone Marrow Transplantation for Tolerance Induction: Requirements • Recipient treatment must have minimal toxicity • Must work for mismatched transplants • Graft-versus-host-disease (GVHD) unacceptable. GVHD is the major complication of bone marrow transplantation, and precludes mismatched transplantation.

  5. Recipient Donor USING STEM CELLS TO INDUCE TOLERANCE 3) New T cells mature and become “educated” in the recipient thymus gland. 1)Treatments are given to block peripheral and intrathymic rejection of donor hematopioetic cells (e.g. anti-T cell mAbs, thymic RTX). Donor stem cells cells are given i.v. 4) The emerging T cells that repopulate the immune system are tolerant of donor and recipient. A donor organ is accepted and there is no GVHD. Blood cells are a mixture of donor and host (mixed chimera) 2) Donor stem cells go to recipient marrow. Stem cells in the marrow send progeny to the recipient thymus.

  6. BMT with T cell costimulatory blockade 3 Gy TBI day 0 15x10^6 B10.A bone marrow cells i.v. (fully MHC-mismatched, unseparated day 0) C57BL/6 anti-CD40L-mAb(0.5mg i.p., day 0) CTLA4Ig (0.5mg i.p., day +2) Wekerle et al, JEM 1998,187:2037

  7. Donor-Specific Skin Graft Tolerance in Recipients of Non-Myeloablative BMT with Costimulatory Blockade 100 80 donor 60 Percent Graft Survival 40 third party 20 n=14 0 0 20 40 60 80 100 120 140 160 Days post Skin-Grafting

  8. Bone Marrow/Stem Cell Transplantation • The only known cure for many types of leukemia and lymphoma. • Requires an HLA closely matched donor because of the complication of graft-versus-host disease (GVHD). • Even with unrelated donors, about half of the patients whose only hope for cure is BMT do not have a donor.

  9. GVHD • Major complication of BMT • Caused by donor T lymphocytes that see recipient antigens as “non-self” • Disease of skin, liver, intestines • Prevented by marrow T cell depletion, but this increases relapse rates, because donor T cells also eradicate leukemia cells

  10. Our Goal • To perform HLA mismatched transplants without GVHD. • To use the GVH “response” (GVHR) to attack leukemia/lymphoma without producing GVHD. We have discovered that GVHR≠GVHD. • This will allow even better cure rates than are seen with matched transplants.

  11. Our Strategy • Stimulate GVHR • Confine GVHR to the tissues where leukemias and lymphomas reside (blood and lymphoid tissues). • i.e. avoid migration of GVHR to skin, gut liver

  12. Step 1: Bone marrow transplant with less toxic recipient treatment that includes antibodies. Donor marrow is T cell depleted Blood cells are a mixture of donor and host: Mixed chimerism is achieved without GVHR Wait 1-2 months. Inflammation from preparative treatment subsides. Step 2: Infuse donor T cells. Donor T cells interact with “presenting cells” of mixed chimera to maximize GVHR Donor T cells are armed to kill tumor cells that express recipient antigens. They stay inside the blood and lymph, where tumor is. T cells don’t go to skin/gut/liver. There is no GVHD. Tumor is killed

  13. 42 y.o. male with disseminated Hodgkin’s Disease, refractory to chemo and radiation therapy. Received a BMT with our protocol in Sept, 1999. Results: No GVHD, complete remission. 1yr post-transplant Pre-transplant

  14. Rationale: Combined Matched Related Donor Bone Marrow and Kidney Transplantation in Multiple Myeloma With Kidney Failure • Allogeneic BMT is the only known cure for MM. Complication rates are high with standard allogeneic BMT. • Kidney failure is a common complication of MM, but the malignancy usually precludes kidney transplantation. • Successful allogeneic BMT with less toxic conditioning induces transplantation tolerance (animal models). • MGH investigators have developed a less toxic BMT protocol that is safe and effective in MM. • Less toxic BMT combined with kidney transplantation from the same donor might induce tolerance while curing the myeloma.

  15. Step 1: Bone marrow and kidney transplant with less toxic recipient treatment. Blood cells are a mixture of donor and host: Mixed chimerismand tolerance to the kidneyis achieved. Wait 1-2 months. Step 2: Infuse donor T cells. Donor T cells interact with “presenting cells” of mixed chimera to maximize GVHR Donor T cells are armed to kill tumor cells that express recipient antigens. Tumor is killed

  16. Combined Kidney and Bone Marrow Transplant: Patient 1 • 55-year-old woman presented in December, 1996 with ESRD due to multiple myeloma. • Rx: Hemodialysis, chemotherapy • September, 1998: combined kidney and bone marrow transplant from HLA-identical sister. • 2005: pt in remission from myeloma; normal kidney function, off all immunosuppression since December, 1998.

  17. CyA Discontinued Days post-transplant Clinical course of patient 1

  18. Applying our Strategy to Mismatched Transplants • A greater challenge, because T cell depleted mismatched marrow is harder to engraft , especially when less toxic recipient treatment is given • We have developed protocols achieving engraftment of mismatched, T cell-depleted marrow without GVHD. • We have obtained proof of principle that our strategy can work in the mismatched setting.

  19. POTENTIAL DONOR SPECIES Swine Advantages Availability Breeding Characteristics Disadvantages Phylogenetic distance Natural (anti-GAL) antibodies

  20. GENETIC ENGINEERING OF PIGS AS XENOGRAFT DONORS DNA • Transgenics • Complement inhibition • DAF • CD46 • CD59 • Fucosyl transferase • Growth factors • pIL-3, pSCF • Human GF receptors • MHC genes • Class I (NK inhibition) • Knock-outs • 1,3-galactosyl transferase Fertilized egg

  21. First GalT-KO miniature swine born November 2002 From: TBRC and Immerge BioTherapeutics, Boston

  22. Replacement of Recipient Thymus With a Xenogeneic Thymus in Thymectomized, T Cell-Depleted Mice Days –6,-1, +7, +14 Anti - CD4 Anti - CD8 mAbs Thymectomize Reconstituted murine CD4 compartment. Tolerance to donor pig. Normal mouse Day 0: Implant 1mm3 fetal miniature swine thymus tissue under kidney capsule

  23. Zhao et al, Nature Medicine 1996, 2:1211

  24. Tolerance by Thymus Transplantation 2. Thymokidney transplantation From: TBRC and Immerge BioTherapeutics, Boston

  25. Creatinine levels B134 (Thymokidney – Steroid free regimen) 10 9 8 7 6 5 Cr(mg/dl) KBx laparotomy 4 3 2 1 0 0 7 14 21 28 35 42 49 56 63 70 77 POD From: TBRC and Immerge BioTherapeutics, Boston

  26. B134 kidney graft biopsy on POD60 x200 Normal kidney Kidney graft was pink No spot hemorrhage From: TBRC and Immerge BioTherapeutics, Boston

  27. Summary of Heart and Kidney Transplants from the first available GalT-KO Pigs • Do not undergo HAR • Do not require antibody absorption nor • complement inhibition • With standard immunosuppression, organ survivals improved - modestly but consistently • With kidney plus thymus tolerance strategy, • survivals increased from maximum of 30 days to >83 days

  28. ACKNOWLEDGEMENTS MGH • BMT Unit (Spitzer, McAfee, Dey, Ballen, et al.) • Transplant Unit (Cosimi, Kawai, Delmonico, Ko, Hertl, et al.) • TBRC (Sachs, Sykes, Yamada, et al.) • Pathology (Colvin, Saidman, et al.) • Infectious Disease (Fishman, Basgoz, et al.) • Renal (Rubin, Williams, Goes, Wong, et al.) • Wellman Photomedicine Laboratories (Lin et al.) OUTSIDE • ITN (NIH) • Biotransplant/Immerge • Medimmune

  29. CONTRIBUTORS: MOUSE STUDIES BMT Section/ Transplantation Biology Research Center Ronjon Chakraverty Hyeon-Seok Eom Markus Mapara Thomas Fehr Yasuo Takeuchi Josef Kurtz Denise Pearson Juanita Shaffer Jennifer Buchli Tim Hogan Peter Cotter Guiling Zhao Richard Hsu Wellman Center for Photomedicine Daniel Cote Costas Pitsillides Charles Lin

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