Islet cell replacement and transplantation immunology in a mouse strain with inducible diabetes

Abstract

Improved models of experimental diabetes are needed to develop cell therapies for diabetes. Here, we introduce the B6 RIP-DTR mouse, a model of experimental diabetes in fully immunocompetent animals. These inbred mice harbor the H2b major histocompatibility complex (MHC), selectively express high affinity human diphtheria toxin receptor (DTR) in islet β-cells, and are homozygous for the Ptprca (CD45.1) allele rather than wild-type Ptprcb (CD45.2). 100% of B6 RIP-DTR mice rapidly became diabetic after a single dose of diphtheria toxin, and this was reversed indefinitely after transplantation with islets from congenic C57BL/6 mice. By contrast, MHC-mismatched islets were rapidly rejected, and this allotransplant response was readily monitored via blood glucose and graft histology. In peripheral blood of B6 RIP-DTR with mixed hematopoietic chimerism, CD45.2 BALB/c donor blood immune cells were readily distinguished from host CD45.1 cells by flow cytometry. Reliable diabetes induction and other properties in B6 RIP-DTR mice provide an important new tool to advance transplant-based studies of islet replacement and immunomodulation to treat diabetes.

Curative islet and hematopoietic cell transplantation in diabetic mice without toxic bone marrow conditioning

“…To investigate if combined HCT and islet transplantation could rescue overtly diabetic recipients across the barrier of full MHC mismatch, we used B6 RIP-DTR mice ( Bhagchandani et al, 2022 ). These harbor the Ins2-HBEGF transgene and are homozygous for Ptprc a (CD45.1).…”

“…Female and male B6 CD45.1 (Stock #: 002014), BALB/c (Stock #: 000651), and FVB (Stock #: 001800) mice 7–8 weeks old were purchased from The Jackson Laboratory (Bar Harbor, ME). B6 RIP-DTR mice were generated and maintained by our group ( Bhagchandani et al, 2022 ). Males were used at 16–20 weeks old, and females were used at 8–10 weeks old.…”

Human stem cell derived beta-like cells engineered to present PD-L1 improve transplant survival in NOD mice carrying human HLA class I

“…Others have shown that xenotransplantation of stem cell derived human beta cells into immune competent mice are fully rejected (no surviving beta cells) within one week (23). Allotransplantation of murine pancreatic islets into nonchemically induced diabetic mice with mis-matched MHC Class I also reject by 4-10 days (56,(65)(66)(67)(68)(69). In overtly diabetic NOD mice, syngeneic NOD islet grafts in the kidney capsule take longer to reject, approximately 8-12 days (54, 70-72).…”