Anti-TCR mAb induces peripheral tolerance to alloantigens and delays islet allograft rejection in autoimmune diabetic NOD mice.
BACKGROUND
Clinical application of islet transplantation to treat type 1 diabetes has been limited by islet allograft destruction by both allogeneic and autoimmune diabetogenic T-cell responses. The current study aims at determining whether an anti-T-cell receptor (TCR) monoclonal antibody (mAb) has potential as a novel and potent induction immunotherapy for islet transplantation.


METHODS
We have investigated the therapeutic efficacy and mechanisms of action of anti-TCR therapy in four different murine models, which comprise either allo- or autoimmune responses alone or both together.


RESULTS
T-cell response to islet allografts was potently abrogated by a brief treatment with an anti-TCRβ mAb (clone H57-597), resulting in long-term survival of BALB/c islet allografts in streptozotocin-induced diabetic B6 mice. Moreover, transient anti-TCR treatment permanently prevented BALB/c skin allograft rejection on Rag1 B6 recipients that were reconstituted with Foxp3 cell-depleted B6 splenocytes, but did not impair the reconstituted cells' ability to reject the later transplanted C3H skin allografts (transplanted at 120 days after BALB/c skin grafting). Transient anti-TCR treatment was also able to completely prevent diabetes onset in NOD.SCID.γc mice that were transferred with lymphocytes from diabetic NOD mice. Next, transient anti-TCR treatment significantly prolonged the survival of transplanted BALB/c islets in overtly diabetic NOD mice, which comprise both allogeneic and autoimmune diabetogenic T-cell responses to the transplanted islets.


CONCLUSIONS
Overall, anti-TCR mAb induced peripheral tolerance to specific alloantigens even in the absence of Foxp3-expressing natural regulatory T cells. These findings reveal the potential for using TCR-targeting mAbs as induction immunotherapy for islet transplantation.
1 Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, OH. 2 Organ Transplant Center, 1st Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 3 Transplant Immunology Center, Houston Methodist Research Institute, Houston, TX. 4 Address correspondence to: Stanislaw M. Stepkowski, M.D., and Dr. Wenhao Chen, Ph.D., Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, 3000 Arlington Avenue, HEB 263A, Toledo, OH 43614.
Ronghai
R
Deng
Mithun
M
Khattar
Aini
A
Xie
Paul M
PM
Schroder
Xiaoshun
X
He
Wenhao
W
Chen
Stanislaw M
SM
Stepkowski
D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000276:immunology / Q000601:surgery*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology / Q000601:surgery*; D051858:Forkhead Transcription Factors / Q000276:immunology; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects; D007519:Isoantigens / Q000097:blood / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D016038:Skin Transplantation / Q000009:adverse effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects*; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007519:Isoantigens; D011948:Receptors, Antigen, T-Cell