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.
The goal of this proposal is to evaluate the potential of local delivery of mesenchymal stem cells (MSCs) to induce immunosuppression and allograft acceptance in pancreatic islet cell and solid organ transplantation. The applicant hypothesizes that local delivery of MSCs will be more effective than systemic delivery, which has been tested in clinical trials without success. The applicant proposes four Specific Aims: (1) to define biomarkers of immunomodulatory potency that will allow classification of different MSCs; (2) to compare the tolerigenic properties of local versus systemic administration of MSCs in allograft transplant models; (3) to translate these studies toward clinical application by testing the potential synergy of MSCs and immunosuppressive agents; and (4) to examine the effect of acute and chronic infections on graft acceptance, immune modulation, and the competence of host defense.
Reviewers did not find this proposal to be particularly novel. They noted that studies similar to those proposed, particularly in Aims 1 and 2.1, have been carried out by other groups. Reviewers did appreciate the novelty of Aim 4, as well as the creative approach proposed for monitoring islet cell destruction. They acknowledged the widespread interest in using MSCs as an off-the-shelf, tolerigenic therapeutic and the potential significance of such a product. However, they noted that human trials of MSCs have thus far failed to demonstrate tolerance induction and thought it was speculative to suggest that local delivery of MSCs would alter this finding. In general, reviewers found this proposal unlikely to have a major impact in the field.
The reviewers found the research plan to be poorly described and lacking detail. They also raised several concerns about the experimental design. With regard to Aim 1, reviewers noted that molecular profiling is mentioned, but little detail is provided, making it difficult to evaluate the value of these studies. With regard to Aim 2, they cautioned that intraperitoneal injection would serve as a poor systemic control, as MSCs injected in this fashion tend to clump in the abdomen rather than distributing systemically. The applicants plan to analyze multiple tissues following MSC engraftment under the kidney capsule; reviewers were puzzled by the omission of the renal draining lymph node (a site of potential MSC drainage), which is standard practice in this field. Aim 3 was judged to be the weakest of the four. While reviewers acknowledged that establishing the ideal immunosuppressive regimen for clinical application is a laudable goal, they were skeptical that data generated in the preclinical model in this Aim would translate meaningfully to humans. Reviewers felt that critical details were missing for Aim 3, such as the type of anti-CD3 antibody. They questioned the rationale for using CD4-depleting antibodies. Finally, the applicant did not offer a clear rationale for using a third immunosuppressive agent, in addition to the proposed drug and MSCs.
Reviewers praised the quality of the Principal Investigator (PI), Partner PI and assembled research team. They noted that the team leaders are highly accomplished and have track records of outstanding achievement with the proposed models and in the study of transplantation. Reviewers were concerned, however, that much of the MSC expertise resides with the Partner PI, and the logistics of international shipping of samples and tissues may be daunting.
Overall, while reviewers appreciated the high quality of the research team and certain novel aspects of the proposal, they described the research plan as lacking detail and were not convinced it would have a major impact on the field.