The objective of this Program Project is to improve outcomes following heart or lung transplantation by clarifying the mechanisms involved in donor-specific tolerance induction. Previous studies funded by this Program Project have provided the basis for successfully extending a tolerance induction approach using mixed chimerism to patients who received simultaneous kidney and bone marrow transplants from living donors. Our hypothesis is that with further mechanistic study, tolerance induced through mixed chimerism will prove applicable to recipients of deceased donor organs making tolerance accessible to heart and lung allograft recipients. The integrating themes in this Program are that 1) targeting newly recognized barriers to tolerance will allow us to alter the balance of an alloresponse away from alloaggression and towards deletion/regulation leading to long-term tolerance, 2) humoral responses and proinflammatory states are particularly detrimental to tolerance induction and may be important confounding factors limiting the duration of the state of mixed chimerism and 3) durable mixed chimerism will likely be required for tolerance in heart and lung recipients because, unlike kidneys, thoracic organs do not appear capable of maintaining tolerance once chimerism disappears. In the specific aims of each Project, the contributions of allo-, auto- and natural antibodies to graft loss after mixed chimerism induction are recognized and addressed in an innovative and complementary manner. Likewise, the deleterious effects of proinflammatory molecules are considered throughout the program and addressed with innovative and complementary approaches. We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation.
The survival of human recipients of heart and lung transplants is limited by rejection and by complications of anti-rejection drugs. The objective of this proposal is to induce a state of immune tolerance in the recipient, which "tricks" the immune system into seeing the foreign graft as its own tissue, so that the organ is not rejected without the need for drugs. This would greatly improve the outcomes of heart and lung transplants.
|Tonsho, Makoto; Michel, Sebastian; Ahmed, Zain et al. (2014) Heart transplantation: challenges facing the field. Cold Spring Harb Perspect Med 4:|
|Haspot, F; Li, H W; Lucas, C L et al. (2014) Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells. Am J Transplant 14:49-58|
|Kawai, Tatsuo; Sachs, David H; Sykes, Megan et al. (2013) HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 368:1850-2|
|Madariaga, M L; Michel, S G; Tasaki, M et al. (2013) Induction of cardiac allograft tolerance across a full MHC barrier in miniature swine by donor kidney cotransplantation. Am J Transplant 13:2558-66|
|Yamada, Y; Boskovic, S; Aoyama, A et al. (2012) Overcoming memory T-cell responses for induction of delayed tolerance in nonhuman primates. Am J Transplant 12:330-40|
|Nadazdin, Ognjenka; Boskovic, Svjetlan; Wee, Siew-Lin et al. (2011) Contributions of direct and indirect alloresponses to chronic rejection of kidney allografts in nonhuman primates. J Immunol 187:4589-97|
|Alessandrini, Alessandro; De Haseth, Stephanie; Fray, Michael et al. (2011) Dendritic cell maturation occurs through the inhibition of GSK-3?. Cell Immunol 270:114-25|
|Nadazdin, Ognjenka; Abrahamian, Gregory; Boskovic, Svjetlan et al. (2011) Stem cell mobilization and collection for induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys. J Surg Res 168:294-300|
|Nadazdin, Ognjenka; Boskovic, Svjetlan; Murakami, Toru et al. (2011) Host alloreactive memory T cells influence tolerance to kidney allografts in nonhuman primates. Sci Transl Med 3:86ra51|
|Veillette, Gregory R; Sahara, Hisashi; Meltzer, Andrew J et al. (2011) Autoimmune sensitization to cardiac myosin leads to acute rejection of cardiac allografts in miniature swine. Transplantation 91:1187-91|
Showing the most recent 10 out of 236 publications