Beth Israel Deaconess Medical Center
Center for Life Science (CLS) Building
3 Blackfan Circle, Room 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.
- Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006 May 11; 441(7090) 235-8.
- Strom TB. Rejection--more than the eye can see. N Engl J Med. 2005 Dec 1;353(22):2394-6.
- Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J, Strom TB, Zheng XX, Noelle RJ. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 2006 Aug 31; 442 (7106): 997-1002.
- Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005 Dec;6(12):1245-52.
- Chakravarti S, Sabatos CA, Xiao S, Illes Z, Cha EK, Sobel RA, Zheng XX, Strom TB, Kuchroo VK. Tim-2 regulates T helper type 2 responses and autoimmunity. J Exp Med. 2005 Aug 1;202(3):437-44. Epub 2005 Jul 25. Erratum in: J Exp Med. 2005 Sep 19;202(6):877.
Immunology webpage updated 12/02/2009