title: Evaluation for synergistic suppression of T cell responses to minor histocompatibility antigens by chloroquine in combination with tacrolimus and a rapamycin derivative, SDZ-RAD.
abstract: The 4-aminoquinolines, chloroquine and hydroxychloroquine, can suppress chronic graft-versus-host disease (GVHD) following blood and marrow transplantation (BMT) in mice and humans, respectively. We hypothesized that chloroquine in combination with tacrolimus and the rapamycin derivative SDZ-RAD can synergistically suppress T cell responses and antigen-presenting cell (APC) function in vitro. We used the APC-dependent C57BL/6 anti-BALB.B T cell response and APC-independent anti-CD3epsilon antibody-induced response to evaluate the role of synergism between chloroquine and tacrolimus or SDZ-RAD on each component of a T cell response to minor histocompatibility antigens. We found that chloroquine with tacrolimus had a greater synergistic suppression of APC-dependent compared to the APC-independent T cell responses, with a combination index (CIx) for 50% inhibition by mean effect analysis of 0.16 and 0.50, respectively (a lower number indicates greater suppression). By contrast, chloroquine with SDZ-RAD had a similar CIx between the two responsed 0.50 vs0.45) suggesting only T cell suppression. Synergy between chloroquine and SDZ-RAD involved a direct effect on T cell cytokine production, whereas synergism between chloroquine and tacrolimus was due to an effect on both T cells and APCs. We conclude that the renal-sparing 4-aminoquinolines may be used syneristically with immunosuppressive drugs currently used for BMT.
authors.affiliation: Department of Pediatric Hematology and Oncology, Chang Gung Children's Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: C-C
authors.initials: CC
authors.lastname: Hsiao
authors.forename: W N
authors.initials: WN
authors.lastname: Su
authors.forename: F
authors.initials: F
authors.lastname: Forooghian
authors.forename: S
authors.initials: S
authors.lastname: Bader
authors.forename: J
authors.initials: J
authors.lastname: Rempel
authors.forename: K T
authors.initials: KT
authors.lastname: HayGlass
authors.forename: A
authors.initials: A
authors.lastname: Gilman
authors.forename: K R
authors.initials: KR
authors.lastname: Schultz
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D000068338:Everolimus; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015778:Minor Histocompatibility Antigens; D011994:Recombinant Proteins; D002738:Chloroquine; D000068338:Everolimus; D020123:Sirolimus; D016559:Tacrolimus