IL-7 Mediated Homeostatic Expansion of Human CD4+CD25+FOXP3+ Regulatory T Cells After Depletion With Anti-CD25 Monoclonal Antibody.
The maintenance or expansion of regulatory T (Treg) cells has a fundamental role in the achievement of immunological tolerance after transplantation. Here we aimed to determine mechanisms of human Treg cell depletion and reconstitution after anti-CD25 monoclonal antibody (mAb) treatment.



Seventeen patients with type 1 diabetes who received pancreatic islet transplantation and anti-CD25 mAb as induction therapy were studied.



We observed an almost complete depletion of Treg cells after injection of anti-CD25 mAb. The kinetic of Treg cell depletion did not parallel the disappearance of CD25+ T cells as CD25 is also rapidly downregulated and internalized. Regulatory T cell reconstitution is completed within 6 months posttransplantation and appeared to be driven by IL-7-mediated homeostatic T cell proliferation. Anti-CD25 mAb treatment sensitizes Treg cell to the biological effect of IL-7, possibly rendering more common γc-chain available to interact with CD127. Homeostatic Treg cell proliferation is resistant to the inhibitory effect of rapamycin and FK506 but can be blocked by the presence of mycophenolate mofetil.



Our data suggest that a compensatory mechanism of IL-7-mediated homeostatic proliferation can restore the inhibitory network of Treg cell after anti-CD25 induction therapy in islet allotransplantation.
1 San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy. 2 FRACTAL, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Debora
D
Vignali
Clara-Marie
CM
Gürth
Silvia
S
Pellegrini
Valeria
V
Sordi
Federico
F
Sizzano
Lorenzo
L
Piemonti
Paolo
P
Monti
D000328:Adult; D064591:Allografts; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D000077552:Basiliximab; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000601:surgery*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D051858:Forkhead Transcription Factors / Q000097:blood / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D053631:Interleukin Receptor Common gamma Subunit / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood / Q000276:immunology*; D015851:Interleukin-7 / Q000494:pharmacology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016559:Tacrolimus / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; C507941:IL2RG protein, human; C508605:IL7 protein, human; D007166:Immunosuppressive Agents; D053631:Interleukin Receptor Common gamma Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins; D000077552:Basiliximab; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus