The Transplant Institute
Beth Israel Deaconess Medical Center
Center for Life Science (CLS) Building
3 Blackfan Circle, East Campus, CLS 608
Boston, MA 02115
The pool size hypothesis, a Manichean view point, and our point of reference. The T cell response to MHC mismatched allografts includes both the unusually large CD4+ and CD8+ pool of graft destroying effector T cells and a much smaller pool of graft protecting suppressor of regulatory T cells. The outcome of the allograft response, rejection or tolerance, is determined the nature of the T cells, effector or regulatory that are ascendant in the allograft recipient (Strom TB, 2004). The functional ascendancy of effector T cells causes rejection while the functional ascendancy of regulatory T cells in an immunosuppressive drug-free host creates tolerance. In addition to the numeric superiority of effector T cells, effector T cells respond to antigen with far greater speed than regulatory T cells. The allograft response has been crafted to swiftly reject the allograft. In the absence of effective immunosuppression rejection is the almost inevitable outcome. Tolerance is even more difficult to achieve than long-term drug-free engraftment.
Therapeutic application of polyclonal or monoclonal anti-pan T cell antibodies can lead to broad, profound and long-lived T cell depletion. A treatment regimen that exclusively targets only recently activated cytopathic donor reactive T cells and spares regulatory T cells might prove to be an exceptionally potent and selective means of fostering long-term engraftment and tolerance. Anti-CD25 antibodies or cytokine (IL-2) toxins, directed against high-affinity tri-molecular IL-2 receptors (IL-2R), which are expressed upon activated, but not resting, T-cells have been employed as immunosuppressive agents. However, these therapies may not readily discriminate between IL-2R+ activated pathogenic T-cells and regulatory T-cells.
To date, there has been a failure to identify tolerizing regimen that appears safe enough for broad clinical application that works in every model system. It seems likely that the most appealing of today's candidate putative tolerizing regimens for human testing will, at best, tolerize some but not all transplant recipients. Needed are powerful surrogate markers for tolerance, markers that identify organs that will elicit signals that will confound tolerance induction and markers that forewarn of impending rejection.
We are currently utilizing a diagnostic strategy that may provide markers that identify organs that will elicit signals that will
confound tolerance induction and markers that forewarn of impending rejection. We believe these developments will occur as outgrowth of our current efforts to test two hypotheses that have practical application for clinical transplantation today 1- surrogate markers for rejection. We have determined, using a transcriptional profiling approach that molecular surrogate markers for allograft rejection exist. Indeed, expression of certain genes anticipates clinically apparent allograft rejection and can identifies patients with on going sub-clinical rejection episodes. In allograft biopsies and circulating blood cells, a well-characterized pattern of T cells activation gene expression events accompanies early acute rejection in sub-clinical as well as clinical models.
1. Fujisaki J, Wu J, Carlson AL, Silberstein L, Putheti P, Larocca R, Gao W, Saito TI, Celso CL, Tsuyuzaki H, Sato T, Cote Sykes M, Strom TB, Scadden DT, Lin CP. In vivo imaging of T(reg) cells providing immune privilege to the haematopoietic stem-cell niche. Nature 2011. 474(7350): 216-219.
2. Fan Z, Spencer JA, Lu Y, Pitsillides CM, Singh G, Kim P, Yun SH, Toxavidis V, Strom TB, Lin CP, Koulmanda M. In vivo tracking of 'color-coded' effector natural and induced regulatory T cells in the allograft response. Nat Med 2010. 16(6):718-722.
3. Hanidziar D, Koulmanda M, Strom TB. Creating transplant tolerance by taming adverse intragraft innate immunity. F1000 Biol Rep 2010. 2: 83.
4. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007. 204(6): 1257-1265.
5. Koulmanda M, Bhasin M, Hoffman L, Fan Z, Qipo A, Shi H, Bonner-Weir S, Putheti P, Degauque N, Libermann TA, Auchincloss H Jr., Flier JS, Strom TB. Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. Proc Natl Acad Sci U S A 2008. 105(42): 16242-16247.
6. Degauque N, Mariat C, Kenny J, Zhang D, Gao W, Vu MD, Alexopoulos S, Oukka M, Umetsu DT, DeKruyff RH, Kuchroo V, Zheng XX, Strom TB. Immunostimulatory Tim-1-specific antibody deprograms Tregs and prevents transplant tolerance in mice. J Clin Invest 2008. 118(2): 735-741.
Last Update: 12/13/2012