A peptide-major histocompatibility complex II chimera favors survival of pancreatic beta-islets grafted in type 1 diabetic mice.
BACKGROUND
Transplantation of pancreatic islets showed a tremendous progress over the years as a promising, new therapeutic strategy in patients with type 1 diabetes. However, additional immunosuppressive drug therapy is required to prevent rejection of engrafted islets. The current immunosuppressive therapies showed limited success in maintaining long-term islet survival as required to achieve insulin independence in type 1 diabetes, and they induce severe adverse effects. Herein, we analyzed the effects of a soluble peptide-major histocompatibility complex (MHC) class II chimera aimed at devising an antigen-specific therapy for suppression of anti-islet T cell responses and to improve the survival of pancreatic islets transplants.


METHODS
Pancreatic islets from transgenic mice expressing the hemagglutinin antigen in the beta islets under the rat insulin promoter (RIP-HA) were grafted under the kidney capsule of diabetic, double transgenic mice expressing hemagglutinin in the pancreas and T cells specific for hemagglutinin (RIP-HA, TCR-HA). The recipient double transgenic mice were treated or not with the soluble peptide-MHC II chimera, and the progression of diabetes, graft survival, and T cell responses to the grafted islets were analyzed.


RESULTS
The peptide-MHC II chimera protected syngeneic pancreatic islet transplants against the islet-reactive CD4 T cells, and prolonged the survival of transplanted islets. Protection of transplanted islets occurred by polarization of antigen-specific memory CD4 T cells toward a Th2 anti-inflammatory response.


CONCLUSIONS
The peptide-MHC II chimera approach is an efficient and specific therapeutic approach to suppress anti-islet T cell responses and provides a long survival of pancreatic grafted islets.
Casares
Sofia
S
Department of Microbiology, Mount Sinai School of Medicine, New York, NY, USA.
Lin
Marvin
M
Zhang
Nan
N
Teijaro
John R
JR
Stoica
Cristina
C
McEvoy
Robert
R
Farber
Donna L
DL
Bona
Constantin
C
Brumeanu
Teodor D
TD
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D002678:Chimera / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000601:surgery*; D019281:Dimerization; D004195:Disease Models, Animal; D005802:Genes, MHC Class II / Q000235:genetics*; D006085:Graft Survival / Q000235:genetics* / Q000276:immunology*; D006388:Hemagglutinins / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000473:pathology / Q000517:prevention & control; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000637:transplantation; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics*; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
D006388:Hemagglutinins; D010455:Peptides