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-CD3ε 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.
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References
Jacoboson P, Uberti J, Davis W, Ratanatharathorn V . Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation Bone Marrow Transplant 1998 22: 217 225
Dumont FJ, Melino MR, Staruch MJ et al. The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells J Immunol 1990 144: 1418 1424
Dumont FJ, Staruch MJ, Koprak SL et al. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin Immunology 1990 144: 251 258
Hess DA, Bird IA, Almawi WY, Rieder MJ . The hydroxylamine of sulfamethoxazole synergizes with FK506 and cyclosporin A, inhibiting T-cell proliferation J Pharmacol Exp Ther 1997 281: 540 548
Blazar BR, Taylor PA, Sehgal SN, Vallera DA . Rapamycin, a potent inhibitor of T-cell function, prevents graft rejection in murine recipients of allogeneic T-cell-depleted donor marrow Blood 1994 83: 600 609
Fung JJ, Todo S, Tzakis A et al. Conversion of liver allograft recipients from cyclosporin to FK506-based immunosuppression: benefits and pitfalls Transplant Proc 1991 23: 14 21
Blazar BR, Taylor PA, Sehgal SN, Vallera DA . Rapamycin prolongs survival of murine recipients of fully allogeneic donor grafts when administrated during the graft-versus-host disease process Ann NY Acad Sci 1993 685: 73 85
Schuurman HJ, Cottens S, Fuchs S et al. SDZ RAD, a new rapamycin derivative, synergism with cyclosporin Transplantation 1997 64: 32 35
Schuler W, Sedrani R, Cottens S et al. SDZ RAD, a new rapamycin derivative, pharmacological properties in vitro and in vivo Transplantation 1997 64: 36 42
Schuurman HJ, Schuler W, Ringers J, Jonker M . The macrolide SDZ RAD is efficacious in a nonhuman primate model of allotransplantation Transplant Proc 1998 30: 2198 2199
Bohler T, Waiser J, Budde K et al. The in vivo effect of rapamycin derivative SDZ RAD on lymphocyte proliferation Transplant Proc 1998 30: 2195 2197
Schultz KR, Bader S, Nelson D et al. Immune suppression by lysosomotropic amines and cyclosporine on T-cell responses to minor and major histocompatibility antigens Transplantation 1997 64: 1056 1065
Schultz KR, Bader S, Paquet J, Li W . Chloroquine treatment affects T-cell priming to minor histocompatibility antigens and graft-versus-host disease Blood 1995 86: 4344 4352
Nagai F, Ushiyama K, Kano I et al. Inhibition of calmodulin stimulation of phosphodiesterase and Ca2+, Mg2+-ATPase activities and shape change of erythrocyte ghosts by chloroquine Biochem Pharmacol 1987 36: 3433 3437
Schultz KR, Nelson D, Bader S . Synergy between lysosomotropic amines and cyclosporin A on human T cell responses to an exogenous protein antigen, tetanus toxoid Bone Marrow Transplant 1996 18: 625 631
Dukmans BA, Borne BE, Landewe RB et al. Chloroquine combined with cyclosporine in rheumatoid arthritis: more than the addition of 2 drugs alone J Rheumatol 1996 23: (Suppl. 44) 61 63
Goldman FD, Gilman AL, Hollenback C et al. Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties Blood 2000 95: 3460 3466
Gilman AL, Chan KW, Mogul A et al. Hydroxychloroquine for the treatment of chronic graft-versus-host disease Biol Blood Marrow Transplant 2000 6: 327 334
Yang X, Gieni RS, Mosmann TR, HayGlass KT . Chemically modified antigen preferentially elicits induction of Th1-like cytokine synthesis patterns in vivo J Exp Med 1993 178: 349 353
Gieni RS, Li Y, HayGlass KT . Comparison of 3H-thymidine incorporation with MTT and MTS bioassays for human and murine IL-2 and IL-4 analysis: tetrazolium assays provide markedly enhanced sensitivity J Immunol Meth 1995 187: 85 93
Lam GKY . The differential aspects of the linear isobole in the study of combined action of agents Bull Mathe Biol 1993 55: 295 313
Berenbaum MC . Synergy, additivism, and antagonism in immunosuppression: a critical review Clin Exp Immunol 1977 28: 1 18
Chou T-C . Derivation and properties of Michaelis–Menten type and Hill type equations for reference ligands J Theor Biol 1976 59: 253 276
Kahan BD, Gibbons S, Tejpal N et al. Synergistic interactions of cyclosporine and rapamycin to inhibit immune performances of normal human peripheral blood lymphocytes in vitro Transplantation 1991 51: 232 239
Kahan BD, Chou T, Tejpal N et al. Synergistic effects of cyclosporin analogs-A, D, G, Imm-125- with rapamycin and/or brequinar Transplant Proc 1994 26: 3021 3024
Powell JD, Lerner CG, Schwartz RH . Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation J Immunol 1999 162: 2772 2784
Vogelsang GB . How I treat chronic GVHD Blood 2001 97: 1196 1201
Quesniaux VFJ, Wehrli S, Steiner C et al. The immunosuppressant rapamycin blocks in vitro responses to hematopoietic cytokines and inhibits recovering but not steady-state hematopoiesis in vivo Blood 1994 84: 1543 1552
Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Vallera DA . Rapamycin inhibits the generation of graft-versus-host disease- and graft-versus-leukemia-causing T cells by interfering with the production of Th1 or Th1 cytotoxic cytokines J Immunol 1998 160: 5355 5365
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Hsiao, CC., Su, W., Forooghian, F. et al. Evaluation for synergistic suppression of T cell responses to minor histocompatibility antigens by chloroquine in combination with tacrolimus and a rapamycin derivative, SDZ-RAD. Bone Marrow Transplant 30, 905–913 (2002). https://doi.org/10.1038/sj.bmt.1703727
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DOI: https://doi.org/10.1038/sj.bmt.1703727
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