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

Preksha Bhagchandani; Charles A Chang; Weichen Zhao; Luiza Ghila; Pedro L Herrera; Simona Chera; Seung K Kim

doi:10.1038/s41598-022-13087-3

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

Sci Rep. 2022 May 31;12(1):9033. doi: 10.1038/s41598-022-13087-3.

Authors

Preksha Bhagchandani^#¹, Charles A Chang^#¹, Weichen Zhao¹, Luiza Ghila², Pedro L Herrera³, Simona Chera², Seung K Kim^{4

5

6

7

8}

Affiliations

¹ Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
² Department of Clinical Science, University of Bergen, Bergen, Norway.
³ Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
⁴ Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA. seungkim@stanford.edu.
⁵ Department of Medicine (Endocrinology Division), Stanford University School of Medicine, Stanford, CA, 94305, USA. seungkim@stanford.edu.
⁶ Department of Pediatrics (Endocrinology Division), Stanford University School of Medicine, Stanford, CA, 94305, USA. seungkim@stanford.edu.
⁷ Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, 94305, USA. seungkim@stanford.edu.
⁸ JDRF Center of Excellence, Stanford University School of Medicine, Stanford, CA, 94305, USA. seungkim@stanford.edu.

^# Contributed equally.

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 H2^b major histocompatibility complex (MHC), selectively express high affinity human diphtheria toxin receptor (DTR) in islet β-cells, and are homozygous for the Ptprc^a (CD45.1) allele rather than wild-type Ptprc^b (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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Diabetes Mellitus, Experimental* / therapy
Islets of Langerhans Transplantation*
Islets of Langerhans*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Transplantation Immunology

Abstract

Publication types

MeSH terms

Grants and funding