Funding opportunities

Immune tolerance induction for islet graft in pancreas of autoimmune diabetic recipient

Funding Type: 
Transplantation Immunology
Grant Number: 
RM1-01745
Funds requested: 
$1 101 712
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Type 1 diabetes (T1D) is an autoimmune disease in which a patient’s immune system mistakenly recognizes the insulin-producing beta cells of the pancreas as foreign and kills them. Transplantation of pancreatic islets from cadaver donors into the liver of a patient can be a curative therapy for severe T1D. However, there are several obstacles to this therapy, including 1) rejection of donor islets; 2) lack of an appropriate graft site because islet grafts in the liver gradually become dysfunctional even without rejection; 3) lack of sufficient donor islets. To overcome these obstacles, we need to 1) induce transplantation immune tolerance in which the host will accept the donor islets as his or her own; 2) make the native pancreas usable again; 3) make the host tolerant to beta cells generated from induced pluripotent stem cells (IPSCs), a modern technique that can produce unlimited numbers of beta cells. The use of hematopoietic stem cell transplantation (HCT) to establish an immune system that consists of immune cells from both the host and the donor (mixed chimerism) is the most effective approach for establishing immune tolerance toward to donor islets. However, the classical HCT procedure usually includes irradiation of the patients before transplantation to knockout the host immune system, and the procedure often damages the patient tissues and causes a severe side effect called GVHD in patients with HCT. Therefore, the classical HCT procedure can not be used for establishing mixed chimerism for islet transplantation immune tolerance of T1D patients. Our lab has reported a non-toxic and GVHD-free anti-CD3-based HCT procedure for establishing mixed chimerism and islet transplantation tolerance in a mouse model of human T1D. This procedure can also clean up the inflammation in the pancreas of the T1D patients and allows for returning the islets back to the native pancreas. In order to make this procedure applicable to the therapy of T1D patients, we propose to do the following studies: 1) explore the mechanisms how mixed chimerism mediate the islet transplantation immune tolerance with the T1D mouse model; 2) test whether immune tolerance established with the non-toxic HCT procedure will work for the beta cells generated from mouse embryonic stem cells, an experimental surrogate for human IPSCs; 3) test whether this novel approach can still work in a large animal model that is more similar to humans. This study will provide new insights into mechanisms of how HCT can be used to correct autoimmune disorders in T1D patients and provide immune tolerance to donor- or host-type islets as well as beta cells generated from stem cells. This study may lead to cure of T1D by non-toxic HCT and injection of beta cells generated from donor- or host-type IPSCs back into the native pancreas.
Statement of Benefit to California: 
Islet transplantation is a curative therapy for refractory type 1 diabetes (T1D), however, immuno-rejection, lack of an appropriate graft site, and lack of donor islets are preventing the application of this therapy. Our proposed studies are to develop a non-toxic hematopoietic cell transplantation (HCT) procedure for induction of immune tolerance to islet transplants from cadaveric donors as well as beta cells generated from so called IPSCs, a modern technique that has the potential to produce unlimited numbers of beta cells. In addition, this novel regimen will allow for the pancreas of T1D patients to be the graft site of islets. This study will potentially provide a cure for Californians and people in the world who are suffering from refractory T1D. In addition, the non-toxic HCT procedure can also provide curative therapy for patients with hematological malignancies (i.e. leukemia, lymphoma) or other autoimmune diseases (i.e. sclerodoma, systemic lupus). This study will also have the potential to benefit Californians economically by providing the novel bone marrow stem cell and beta cell based therapy for variety of patients worldwide.
Review Summary: 
Islet transplantation is a curative therapy for human Type 1 diabetes (T1D), which occurs when there is autoimmune destruction of pancreas islet beta cells. However, graft rejection, lack of an appropriate graft site, and donor islet shortages have limited the usefulness of this therapeutic approach. Currently, when donor islet cells are available, they are injected into the liver through the portal vein in immune suppressed T1D patients and these individuals must remain on a life-long immunosuppressive (IS) regimen and most become insulin-dependent again in 3-5 years. This applicants’ long term goal is to develop a nontoxic hematopoietic cell transplantation (HCT) procedure for induction of mixed chimerism for immune tolerance of iPSC-derived beta cells. In this proposal, the applicants propose in Aim 1 to induce mixed chimerism using a non-toxic conditioning regimen described by this group and major histocompatibility complex (MHC) mismatched donor bone marrow (BM) cells in a murine T1D model. The applicant plans to demonstrate that this protocol promotes tolerance to subsequent pancreatic transplant of beta cells derived from murine embryonic stem cells (mESC). Further, in Aim 2, the applicants plan to perform preclinical studies establishing this protocol and its ability to promote mixed chimerism and curative beta cell transplant tolerance in a relevant preclinical animal model. Reviewers agreed that the mixed chimerism approach is not novel since it is a well-established route to immune tolerance and many laboratories are using this approach. However, the use of a conditioning regimen that eliminates the need for radiation, the injection of beta islet cells into the appropriate microenvironment (the pancreas), and the use of mESC-derived beta cells offers some new elements to this approach. Additionally, reviewers valued the use of a preclinical animal model and thought this aspect of the proposed research was highly translational. For this reason, reviewers considered this a potentially important and useful protocol for enabling successful tissue transplantation. The scientific rationale for this proposal is based on research published by the principal investigator (PI) and convincingly supported for the most part by the literature and in preliminary data. The experimental plan for Aim 1 is well described, sound, and logical, although, reviewers did have some minor criticisms of Aim 1. First, the in vivo function of the mESC-derived beta cells that the applicant proposes to use for transplantation is not clear and alternatives plans are not described in the event these cells fail to function. Second, the applicants did not provide specific background information on the proposed murine model. The model as stated in the proposal is good for looking at deletion of autoreactive T cells but does not develop diabetes at high incidence. Finally, reviewers noted that contrary to what is stated in the proposal; mESC-derived cells from the specific murine model have been generated (published by 2 groups in July of last year). Despite these concerns, reviewers were confident that Aim1 could yield meaningful results. Reviewers did not have the same confidence in the feasibility of Aim 2. The research plan for Aim 2 lacked important details that made it difficult for the reviewers to assess the feasibility of the aim. The induction of stable mixed chimerism in the proposed model is highly challenging and quite different from a murine model. The applicant did not address how a conditioning regimen established in a murine model would be applied in the preclinical model nor how the protocol for islet graft transplantation would be established. For example, the applicant did not describe in any detail how the doses of conditioning agents were selected and the alternative dosing options described were vague. Additionally, no description was provided for how cytokine storms in the preclinical model (a significant regulatory concern) would be monitored and avoided. The number of animals needed for Aim 2a and the timeline to determine a viable protocol for mixed chimerism induction were not apparent. There was only one dose of islets proposed and no mention of options if that islet dose is insufficient. It was unclear how the host anti-donor responses will be monitored to determine if the mechanism established in the murine system is observed in the preclinical model. This lack of detail was particularly concerning to reviewers given the criticality of the proposed model. Reviewers thought the PI is highly competent and productive with a clearly successful tract record. Further, the PI has assembled an accomplished research team that provides all the necessary expertise to perform the proposed research. In short, the research team is superb. The PI has recruited a world expert in the proposed preclinical model as a collaborator who is more than capable of carrying out the proposed research. However, given the lack of critical detail in the experimental design in Aim 2, the benefits of this collaboration were absent from the proposal and it was not evident to reviewers that the PI had consulted with this collaborator in designing the proposed experiments. Overall, despite their enthusiasm for the highly translational nature of this proposal and the strong research team, reviewers did not recommend this proposal for funding because of the overriding feasibility concern in the experimental plan.
Conflicts: 

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