1 / 17

THE ENIGMA OF CHIMERISM, THE UNIQUE TOLEROGENICITY OF BONE MARROW AND CLINICAL TOLERANCE

Anthony P. Monaco, M.D. Peter Medawar Professor of Transplantation Surgery Harvard Medical School Beth Israel Deaconess Medical Center Boston, MA. THE ENIGMA OF CHIMERISM, THE UNIQUE TOLEROGENICITY OF BONE MARROW AND CLINICAL TOLERANCE. Suppression. Chimerism. Anergy. Operationally

cicada
Download Presentation

THE ENIGMA OF CHIMERISM, THE UNIQUE TOLEROGENICITY OF BONE MARROW AND CLINICAL TOLERANCE

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Anthony P. Monaco, M.D. Peter Medawar Professor of Transplantation Surgery Harvard Medical School Beth Israel Deaconess Medical Center Boston, MA THE ENIGMA OF CHIMERISM, THE UNIQUE TOLEROGENICITY OF BONE MARROW AND CLINICAL TOLERANCE

  2. Suppression Chimerism Anergy Operationally Tolerant State Costimulatory Blockade Clonal Deletion

  3. The Dichotomy Between Chimerism and Tolerance • Depending on the histocompatibility relationships, neonatallyinjected mice can be chimeras and still reject grafts and chimeric mice can accept grafts but show in vitro alloimmunity. - Streilein JW. Transplantation 1991; 52:1 • Bone marrow from T-cell deficient knockout mice produce a high degree of chimerism but not associated tolerance in wild type mice. - UmemuraA et al. Transplantation 2001; 33:148 • T-cell deficient bone marrow transplants produce significant chimerism in Rhesus monkeys but no tolerance to concurrently transplanted kidney allografts. - RamakrisnanSK et al. Am J Transplant 2012; 12:1755

  4. Chimerism After Solid Organ Transplantation Macrochimerism • occurs after liver, intestinal transplants • causes GVHD and mortality • tolerance rarely results Microchimerism • very frequent • can last for years • no association with outcomes

  5. Optimal Antigen Monaco, Transplant Proc 1970; 2, 489-496

  6. “. . . certain tissues and organs might contain stem cells derived from the bone marrow . . . which could facilitate the induction of tolerance.” Monaco, A.P. and Wood, M.L. Transpl Proc 2:489-496,1970

  7. Suppressor/Regulatory Cells After Antilymphocyte Serum and Bone Marrow Treatment • Lymphocyte depletion with ALS causes non-specific suppressor cells. - Simpson MA et al. Trans Proc 1983; 15:740 • ALS and skin allografting cause donor specific suppressor cells. • ALS, skin grafting and donor bone marrow causes donor derived suppressor T-cells. - Maki T et al. J of Immunology 1981; 127:1433

  8. CANINE RENAL ALLOGRAFT SURVIVAL AFTER ALSAND DONOR BONE MARROW ADMINISTRATION * No clinical or histological evidence of rejection at time of death

  9. Adjuvant Use of Cyclosporine 50mg/kg I.p. qod x 14 days Wood et. al. Transplantation 1988: 46; 449

  10. Dose Response(DBA/2 to B6AF1)

  11. Effect of BM Dose

  12. ChimerismPeripheral Blood

  13. Chimerism in Current Tolerance Protocols

  14. Preliminary Conclusions • Chimerism is a positive biomarker that tolerance induction is likely • Durable chimerism is not required for durable tolerance • Bone marrow infusions are safe (no GVHD) • Tolerance protocols are surprisingly safe • More academic transplant programs should initiate clinical tolerance trials

  15. A Commentary on Man “Man will occasionally stumble over the truth, but most of the time, he will pick himself up and continue on.” Winston Churchill

More Related