Rapamycin monotherapy in patients with type 1 diabetes modifies CD4+CD25+FOXP3+ regulatory T-cells.
OBJECTIVE
Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4(+)CD25(+)FOXP3(+) T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs.


METHODS
nTreg numbers and function were examined in a unique set of patients with type 1 diabetes who underwent rapamycin monotherapy before islet transplantation.


RESULTS
We found that rapamycin monotherapy did not alter the frequency and functional features, namely proliferation and cytokine production, of circulating nTregs. However, nTregs isolated from type 1 diabetic patients under rapamycin treatment had an increased capability to suppress proliferation of CD4(+)CD25(-) effector T-cells compared with that before treatment.


CONCLUSIONS
These findings demonstrate that rapamycin directly affects human nTreg function in vivo, which consists of refitting their suppressive activity, whereas it does not directly change effector T-cell function.
Monti
Paolo
P
Telethon-Juvenile Diabetes Research Foundation Center for Beta Cell Replacement, San Raffaele Scientific Institute, Milan, Italy.
Scirpoli
Miriam
M
Maffi
Paola
P
Piemonti
Lorenzo
L
Secchi
Antonio
A
Bonifacio
Ezio
E
Roncarolo
Maria-Grazia
MG
Battaglia
Manuela
M
D000328:Adult; D015704:CD4 Antigens / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D003131:Combined Modality Therapy; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology / Q000601:surgery*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D008875:Middle Aged; D011300:Preoperative Care; D020123:Sirolimus / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D020123:Sirolimus