title: Rapamycin inhibits production of cytotoxic but not noncytotoxic antibodies and preferentially activates T helper 2 cells that mediate long-term survival of heart allografts in rats.
abstract: Rapamycin (RAPA) induces unresponsiveness toward heart allografts by at least two mechanisms: selective production of noncytotoxic IgG2c-blocking Ab and preferential activation of Th2 cells. RAPA (0.8 mg/kg/day) delivered via a 14-day osmotic pump to Wistar Furth (WF; RT-1u) recipients prolongs Buffalo (BUF; RT-1b) heart allograft survival from a mean survival time (MST) of 6.5 +/- 0.5 days to 75.0 +/- 18.9 days (n = 18; p < 0.001), with 6 of 18 grafts beating for more than 100 days. Recipient sera or their IgG but not IgM fraction, obtained after postgrafting day 40, passively transfer the unresponsive state to sublethally irradiated secondary recipients in a dose-dependent and immunologically-specific fashion. Sera obtained after untreated WF hosts rejected BUF hearts contained IgG moieties of all subclasses that bound to class I MHC BUF epitopes. In contrast, the unresponsive sera contained predominantly non-C'-fixing IgG2c and only marginal amounts of activated (C') fixing IgG1, IgG2a, and IgG2b Ab. The transcription of IL-2, IL-4, and IL-10 mRNAs was assessed using a PCR method. There were similar increases in the levels of IL-2, IL-4, and IL-10 mRNA in heart allografts from both untreated and RAPA-treated recipients on day 5 postgrafting. In contrast, on days 60 and 300 postgrafting heart allografts from RAPA-treated unresponsive recipients showed increased levels of IL-10 and IL-4 but not of IL-2 mRNA, suggesting preferential activation of Th2 cells. Thus, RAPA treatment selectively inhibits the synthesis of C'-binding of IgG subclasses, spares the non C-binding blocking IgG2c Ab, and preferentially activates Th2 cells.
authors.affiliation: Department of Surgery, University of Texas Medical School at Houston 77030.
authors.forename: M
authors.initials: M
authors.lastname: Ferraresso
authors.forename: L
authors.initials: L
authors.lastname: Tian
authors.forename: R
authors.initials: R
authors.lastname: Ghobrial
authors.forename: S M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D015870:Gene Expression; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007116:Immunization, Passive; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007165:Immunosuppression Therapy / Q000379:methods; D008213:Lymphocyte Activation; D008297:Male; D011090:Polyenes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D011915:Rats, Inbred BUF; D011920:Rats, Inbred WF; D020123:Sirolimus; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D016207:Cytokines; D007132:Immunoglobulin Isotypes; D011090:Polyenes; D012333:RNA, Messenger; D020123:Sirolimus