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