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

Summary: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 APCindependent anti-CD3⑀ 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 vs 0.45) 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. Bone Marrow Transplantation (2002) 30, 905-913.

Effectiveness of topical calcineurin inhibitors as monotherapy or in combination with hydroxychloroquine in cutaneous lupus erythematosus

“…Also, the induction of apoptosis was not found to be responsible for the increased suppression achieved by the drug combination, suggesting that possible other effects on APC and T cells take place. 4 Lampropoulos and D'Cruz report that more than 50% of patients with DLE and SCLE may show improvement after 4 weeks of treatment with topical calcineurin inhibitors, making this a potentially safe and effective therapeutic option. 5 In a study by Barikbin et al, pimecrolimus 1% cream had comparable efficacy with betamethasone valerate 0.1% in the treatment of facial DLE, 6 while Sugano et al studied the application of tacrolimus ointment 0.1% to DLE lesions twice daily which resulted in significant improvement of the erythematous plaques after 4-8 weeks.…”

Chloroquine prevention of murine MHC-disparate acute graft-versus-host disease correlates with inhibition of splenic response to CpG oligodeoxynucleotides and alterations in T-cell cytokine production

“…Chloroquine administration in vivo inhibited the ability of antigen-presenting cells (APCs) derived from treated mice to stimulate T-cells reactive against MiHC [15] and MHC [12] antigens and inhibited lipopolysaccharide (LPS)-induced MHC class II expression. Both chloroquine and hydroxychloroquine have the added benefit that they are synergistic with cyclosporine, tacrolimus, and rapamycin analogues [18,19]. A phase II clinical study demonstrated that hydroxychloroquine therapy induced a partial or complete response in 52% of 32 evaluable patients with steroid-refractory chronic GVHD after BMT [20].…”

In Vitro and In Vivo Sirolimus for Modulation of Allogeneic Hematopoietic Stem Cell Transplantation

“…Of note, human DC inhibition did not occur with cyclosporine or FK506 exposure; in fact, an excess of FK506 was effective in reversal of sirolimus-mediated APC inhibition. Although the sum of these murine and human data indicate that sirolimus inhibits APC function through inhibition of antigen presentation, reduction in co-stimulation, and impairment of IL-12 production or IL-12 receptor signaling, it should be noted that other studies have found that calcineurin inhibitors can inhibit APC to a greater degree than sirolimus [36,37].…”