Protection of porcine islet xenografts in mice using sertoli cells and monoclonal antibodies.
BACKGROUND
To remedy the shortage of human donor islets, xenotransplantation of neonatal porcine islets (NPI) provides an attractive alternative source of donor tissue so long as graft rejection can be circumvented. Thus, in this study, we sought to determine whether cotransplantation of NPI with Sertoli cells (SC) combined with a short-course treatment of monoclonal antibody (mAb) could provide long-term islet xenograft survival.


METHODS
NPI alone or NPI cotransplanted with neonatal porcine SC were transplanted into diabetic C57BL/6 mice. These mice were left untreated or were treated with a short course of antileukocyte function associated antigen-1 (LFA-1), anti-CD154, or anti-CD45RB mAb. Blood glucose levels were monitored twice a week to assess graft function. At more than 100 days posttransplantation or on the day of rejection, graft-bearing kidneys were collected for characterization using immunohistochemistry.


RESULTS
None of the untreated control mice transplanted with NPI alone (0/5) or NPI cotransplanted with SC (0/8) achieved normoglycemia. However, of the mice receiving NPI alone, 3 of 7 treated with anti-LFA-1 mAb, 2 of 7 treated with anti-CD154 mAb, and 1 of 7 treated with anti-CD45RB mAb achieved long-term graft survival (>100 days). These proportions improved considerably when NPI were cotransplanted with SC, as 15 of 15 mice treated with anti-LFA-1 mAb, 7 of 8 mice treated with anti-CD154 mAb, and 4 of 9 mice treated with anti-CD45RB mAb achieved long-term graft survival.


CONCLUSIONS
These results show that transient administration of anti-LFA-1 mAb or anti-CD154 mAb is efficacious in prolonging NPI xenograft survival when islets are cotransplanted with SC. Interleukin-4 and Serpina3n may be important mediators of protection observed in this model.
Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
Qahir A
QA
Ramji
Kevin
K
Bayrack
Hossein
H
Arefanian
Marcelo
M
Marcet-Palacios
R Chris
RC
Bleackley
Ray V
RV
Rajotte
Gina R
GR
Rayat
D000209:Acute-Phase Proteins / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D003920:Diabetes Mellitus / Q000097:blood / Q000276:immunology / Q000628:therapy; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D015847:Interleukin-4 / Q000097:blood / Q000276:immunology; D016381:Islets of Langerhans Transplantation; D017493:Leukocyte Common Antigens / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015843:Serpins / Q000097:blood / Q000276:immunology; D012708:Sertoli Cells / Q000637:transplantation*; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology / Q000379:methods
D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; C516624:Serpina3n protein, mouse; D015843:Serpins; C114320:anti-LFA-1 monoclonal antibody; D023201:CD40 Ligand; D015847:Interleukin-4; D017493:Leukocyte Common Antigens