Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas.
EBV-infected B-cell lymphomas are a potentially life-threatening complication in bone marrow and solid organ transplant recipients. Immunosuppressive drugs required to prevent allograft rejection also impair anti-EBV T-cell immunity, thereby increasing the risk of EBV-associated disease. Here we demonstrate that the immunosuppressant rapamycin (RAPA) has a strong antiproliferative effect in vitro on B-cell lines derived from organ transplant recipients with EBV-associated posttransplant lymphoproliferative disorder (PTLD). Furthermore, RAPA significantly inhibits or delays the growth of solid tumors established from EBV-infected B-cell lines in a xenogeneic mouse model of PTLD. RAPA acts via cell cycle arrest, induction of apoptosis, and, most importantly, inhibition of interleukin 10 secretion, a necessary autocrine growth factor. The reduced interleukin 10 production is accompanied by corresponding decreases in the constitutive activation of the growth-promoting transcription factors signal transducer and activator of transcription 1 and 3. Thus, RAPA can limit B-cell lymphoma growth while simultaneously providing immunosuppression to prevent graft rejection in patients who are otherwise at risk for EBV-associated PTLD. Moreover, these findings may have application to other EBV-associated malignancies.
Nepomuceno
Ronald R
RR
Department of Surgery, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305, USA.
Balatoni
Cynthia E
CE
Natkunam
Yaso
Y
Snow
Andrew L
AL
Krams
Sheri M
SM
Martinez
Olivia M
OM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020031:Epstein-Barr Virus Infections / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D053613:Janus Kinase 1; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control / Q000821:virology*; D008297:Male; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism; D014180:Transplantation / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D020123:Sirolimus