A novel clinically relevant approach to tip the balance toward regulation in stringent transplant model.
BACKGROUND
Regulatory T cells (Tregs) actively regulate alloimmune responses and promote transplantation tolerance. Thymoglobulin, a rabbit polyclonal antithymocyte globulin (ATG), is a widely used induction therapy in clinical organ transplantation that depletes peripheral T cells. However, resistance to tolerance induction is seen with certain T-cell depleting strategies and is attributed to alterations in the balance of naive, memory and Tregs. The exact mechanism of action of ATG and its effects on the homeostasis and balance between Tregs and T-effector-memory cells (Tem) are unknown.


METHODS
A novel antibody reagent, rabbit polyclonal anti-murine thymocyte globulin (mATG), generated by the same process used to manufacture thymoglobulin, was used alone or in combination with CTLA4Ig or sirolimus (SRL) in a stringent fully major histocompatibility complex-mismatched murine skin allograft model to study graft survival and mechanisms involved.


RESULTS
mATG depletes T cells but preferentially spares CD25+ natural Tregs which limit skewing of T-cell repertoire toward Tem phenotype among the recovering T cells. T-cell depletion with mATG combined with CTLA4Ig and SRL synergize to prolong graft survival by tipping the Treg/Tem balance further in favor of Tregs by preserving Tregs, facilitating generation of new Tregs by a conversion mechanism and limiting Tem expansion in response to alloantigen and homeostatic proliferation.


CONCLUSIONS
Simultaneous T-cell depletion with ATG and costimulatory blockade, combined with SRL, synergizes to promote regulation and prolong allograft survival in a stringent transplant model. These results provide the rationale for translating such novel combination therapy to promote regulation in primate and human organ transplantation.
D'Addio
Francesca
F
Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Yuan
Xueli
X
Habicht
Antje
A
Williams
John
J
Ruzek
Melanie
M
Iacomini
John
J
Turka
Laurence A
LA
Sayegh
Mohamed H
MH
Najafian
Nader
N
Ansari
M Javeed
MJ
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000961:Antilymphocyte Serum / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006648:Histocompatibility; D006706:Homeostasis; D018796:Immunoconjugates / Q000494:pharmacology; D007156:Immunologic Memory / Q000187:drug effects; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D011817:Rabbits; D020123:Sirolimus / Q000494:pharmacology; D016038:Skin Transplantation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects*; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; C512542:thymoglobulin; D020123:Sirolimus