IDEC-131 (anti-CD154), sirolimus and donor-specific transfusion facilitate operational tolerance in non-human primates.
CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical transplant trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a donor blood transfusion), or mTOR inhibition (e.g., sirolimus), enhances anti-CD154's efficacy. We performed renal transplants in major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients with combinations of the CD154-specific antibody IDEC-131, and/or sirolimus, and/or a pre-transplant donor-specific transfusion (DST). Therapy was withdrawn after 3 months. Triple therapy prevented rejection during therapy in all animals and led to operational tolerance in three of five animals including donor-specific skin graft acceptance in the two animals tested. IDEC-131, sirolimus and DST are highly effective in preventing renal allograft rejection in primates. This apparently clinically applicable regimen is promising for human renal transplant trials.
Preston
Edwin H
EH
Transplantation Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.
Xu
He
H
Dhanireddy
Kiran K
KK
Pearl
Jonathan P
JP
Leopardi
Frank V
FV
Starost
Matthew F
MF
Hale
Douglas A
DA
Kirk
Allan D
AD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001803:Blood Transfusion; D017252:CD3 Complex / Q000096:biosynthesis; D023201:CD40 Ligand / Q000276:immunology*; D006084:Graft Rejection; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007518:Isoantibodies / Q000737:chemistry; D016030:Kidney Transplantation / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000378:metabolism; D008253:Macaca mulatta; D008285:Major Histocompatibility Complex; D011323:Primates; D011494:Protein Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D016038:Skin Transplantation; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D023201:CD40 Ligand; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C470330:toralizumab; D020123:Sirolimus