Despite the success of organ transplantation for the replacement of irreversible injured organs during the last decades, it still faces long term issues because of the need for long-term immunosuppression in order to combat alloreactivity that can cause graft loss. On one hand, chronic immunosuppression expresses general toxicity resulting in diabetes, cardiovascular problems etc and on the other hand long-term inhibition of immune reactivity can support secondary virus-associated cancers and enhance susceptibility to infections. In order to solve the problem of chronic immunosuppression, several systemic protocols for tolerance induction have been developed recently. Unfortunately, systemic tolerance induction protocols that works fine in conventional preclinical models, fail mostly if applied to clinically more relevant animal models or even more in patients. One explanation is the higher intragraft inflammation in patients triggered following transplantation by different well-defined reasons. The same challenge arrives for the putative use of (induced) pluripotent stem cell [iPSC]-derived allografts in the future. Thus, new ways to locally modulate the immune system therewith supporting tolerance induction and minimizing systemic side effects are urgently needed. One interesting approach is the use of mesenchymal stem cells (MSCs) that have been shown to have tolerance-promoting immunomodulatory properties. However, their systemic use in recent clinical trials for targeting autoimmune diseases has not shown promise. One explanation for failing in these trials is the systemic application of MSC used there, so only few cells can reach the region of interest. Here we propose to use MSCs locally at the allograft site using animal models for islet, and heart transplants. We will evaluate how MSCs affect the immune system when given alone in this way and in conjunction with short-term systemic immune modulators. We will also study, how viral infections affect the generation of graft tolerance and how MSCs might affect the way viral infections are handled by the immune system. These studies, which will be realized out through a unique collaboration between [REDACTED] and [REDACTED], should chart novel pathways for tolerance induction using MSCs, which will be instrumental for future transplant strategies with iPSCs.
Statement of Benefit to California:
The benefits for California in line with the mission of CIRM are several-fold:
First, new positions will be generated within California through this 3 year grant proposal. Second, through the fund-matching cooperation with the Collaborative Funding Partner, California CIRM essentially obtains double the impact for its financial investment. Third, the unique cooperation between a well-known clinically oriented immunology team in [REDACTED] and an expert laboratory for in vivo models of immunity and autoimmunity in [REDACTED] will enhance progress and allow us to address the posed questions in more depth and from more angles, than one laboratory could on its own.