Organ transplantation is a critical therapy for patients with irreversible organ damage. Short-term outcomes are excellent, but most patients lose their organs eventually due to chronic immune-mediated injury over time. Ischemia reperfusion injury (IRI) is unavoidable in transplantation and the primary activator of the innate immune response in the early post-transplant period, which enhances the rates of acute and chronic allograft rejection subsequently. Furthermore, a critical worldwide shortage of organs available for transplant exists, which has prompted clinicians to use organs from donors who are older or have greater comorbidity. These organs have much greater susceptibility to ischemic injuries. Therefore, the association of IRI with increased allograft immunogenicity has very broad clinical implications. Costimulatory blockade (CB) has emerged recently as a highly promising therapeutic approach in transplantation with far superior microvascular and metabolic safety profile than calcineurin inhibitors. However, CB is associated with increased rates of acute allograft rejection during the early post-transplantation phase. Our data indicate that IRI abrogates the tolerogenic effect of CB. Therefore, a key unmet need in transplantation is to understand better the mechanisms by which IRI and its activation of the innate immune response potentiates transplant rejection, as novel therapeutic regimens to prevent or ameliorate IRI-induced alloimmunity could assist in reducing chronic rejection. Our main goal is to reveal the underlying mechanisms of augmentation of transplant rejection by IRI. Pursuant to our data, our main hypothesis is that IRI activates alloimmunity by A) increasing the early intra- graft inflammatory response and B) priming the draining lymph node (DLN) of the graft recipient through distinctive microanatomical changes. We have shown that early intra-graft inflammatory responses play a critical role in augmenting alloimmunity. We also propose here for the first-time the use of nanoparticles for targeted delivery of immune therapeutics to the DLN for the reduction of IRI-induced alloimmunity.
In AIM 1, we will examine how induction of autophagy in donor dendritic cells by IRI creates a pro-inflammatory milieu within the organs that augments alloimmunity.
In AIM 2, we will examine the mechanism by which IRI of the grafts primes the DLN microanatomically to amplify the alloimmune response.
In AIM 3, we will develop nanoparticles for the targeted delivery of CB to the DLN for augmentation of their tolerogenic effects in reducing the deleterious effects of IRI.

Public Health Relevance

Organ transplantation has become a life-saving strategy for patients with irreversible organ diseases. However, ischemia reperfusion injury (IRI) of the transplanted organ occurs inevitably following the operation and augments inflammatory responses within the organ markedly, leading to transplant rejection. This project seeks to unveil the mechanisms by which IRI induces this immune response and harness this knowledge to develop novel therapies that will improve transplant outcomes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Kehn, Patricia J
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Brigham and Women's Hospital
United States
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