A novel clinically relevant strategy to abrogate autoimmunity and regulate alloimmunity in NOD mice.
OBJECTIVE
To investigate a new clinically relevant immunoregulatory strategy based on treatment with murine Thymoglobulin mATG Genzyme and CTLA4-Ig in NOD mice to prevent allo- and autoimmune activation using a stringent model of islet transplantation and diabetes reversal.


METHODS
Using allogeneic islet transplantation models as well as NOD mice with recent onset type 1 diabetes, we addressed the therapeutic efficacy and immunomodulatory mechanisms associated with a new immunoregulatory protocol based on prolonged low-dose mATG plus CTLA4-Ig.


RESULTS
BALB/c islets transplanted into hyperglycemic NOD mice under prolonged mATG+CTLA4-Ig treatment showed a pronounced delay in allograft rejection compared with untreated mice (mean survival time: 54 vs. 8 days, P < 0.0001). Immunologic analysis of mice receiving transplants revealed a complete abrogation of autoimmune responses and severe downregulation of alloimmunity in response to treatment. The striking effect on autoimmunity was confirmed by 100% diabetes reversal in newly hyperglycemic NOD mice and 100% indefinite survival of syngeneic islet transplantation (NOD.SCID into NOD mice).


CONCLUSIONS
The capacity to regulate alloimmunity and to abrogate the autoimmune response in NOD mice in different settings confirmed that prolonged mATG+CTLA4-Ig treatment is a clinically relevant strategy to translate to humans with type 1 diabetes.
Vergani
Andrea
A
Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. paolo.fiorina@childrens.harvard.edu
D'Addio
Francesca
F
Jurewicz
Mollie
M
Petrelli
Alessandra
A
Watanabe
Toshihiko
T
Liu
Kaifeng
K
Law
Kenneth
K
Schuetz
Christian
C
Carvello
Michele
M
Orsenigo
Elena
E
Deng
Shaoping
S
Rodig
Scott J
SJ
Ansari
Javeed M
JM
Staudacher
Carlo
C
Abdi
Reza
R
Williams
John
J
Markmann
James
J
Atkinson
Mark
M
Sayegh
Mohamed H
MH
Fiorina
Paolo
P
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000961:Antilymphocyte Serum; D015551:Autoimmunity / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000601:surgery; D004797:Enzyme-Linked Immunosorbent Assay; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D010047:Ovalbumin / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D010047:Ovalbumin; C512542:thymoglobulin
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