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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL018646-35
Application #
8459913
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
35
Fiscal Year
2013
Total Cost
$461,301
Indirect Cost
$138,631
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Chatterjee, Debanjana; Moore, Carolina; Gao, Baoshan et al. (2018) Prevalence of polyreactive innate clones among graft--infiltrating B cells in human cardiac allograft vasculopathy. J Heart Lung Transplant 37:385-393
Gonzalez-Nolasco, Bruno; Wang, Mengchuan; Prunevieille, Aurore et al. (2018) Emerging role of exosomes in allorecognition and allograft rejection. Curr Opin Organ Transplant 23:22-27
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Newton, Ryan H; Shrestha, Sharad; Sullivan, Jenna M et al. (2018) Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat Immunol 19:838-848

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