ReviewInfluence of immunosuppressive drugs on dendritic cells
Introduction
Remarkable advances have been made in clinical transplantation over the past two decades, largely because of major strides in understanding the immune mechanisms involved in transplant rejection and the development of more effective and safer immunosuppressive drugs. Nevertheless, the goal of specific and sustained inhibition of donor-specific immune responses in the absence of both graft pathology and dependence on anti-rejection therapy remains elusive.
In keeping with the fundamental role of T cells in graft rejection, much emphasis in the development of immunosuppressive drugs has been focused on inhibition of T cell activation and proliferation. The mechanisms by which these drugs affect T cells have been investigated in great detail. However, induction of immune responses does not rely solely on T cells, but also on essential and complex interactions between antigen-presenting cells (APC) and T cells. The immune response to organ grafts is believed to be initiated by the presentation of alloantigen by donor and self APC to host T cells, which then differentiate into effector and regulatory cells. Dendritic cells (DC) are rare, ubiquitously distributed, migratory APC, derived from CD34+ bone marrow (BM) stem cells. In addition to having the unique capacity to prime naı̈ve T cells, DC also regulate various effector cell functions and play central roles in modulating the immune response [1], [2]. Donor-derived DC are commonly regarded as the principal instigators of transplant rejection, but considerable evidence also exists for DC tolerogenicity in the context of alloimmune responses [3], [4], [5]. In addition, immature DC and DC manipulated pharmacologically, biologically or genetically to enhance their tolerogenicity in vitro or in vivo can improve outcomes in cell or organ transplantation [3], [4], [5]. Thus, in order to comprehend the mechanism of action of immunosuppressive drugs and their potential for tolerance induction more fully, it is necessary to elucidate their influence on DC development, maturation and function.
In this review, we discuss recently-accumulated information on the effects of currently used immunosuppressive drugs on DC both in vitro and in vivo. While most available information concerns classic (myeloid/monocytoid) DC, evidence is also emerging concerning the influence of immunosuppressive drugs on DC subsets that have been identified in humans and experimental animals.
Section snippets
Azathioprine (AZA)
AZA was the most widely used immunosuppressive drug for prophylaxis of acute rejection in organ transplant recipients until the advent of cyclosporine in 1979. This agent has found increasing use in the treatment of autoimmune diseases. AZA is a pro-drug that is converted to 6-mercaptopurine, which is subsequently metabolized to the pharmacologically active 6-thioguanine nucleotides. These metabolites block the de novo and salvage pathways of purine nucleotide biosynthesis and subsequently,
Cyclosporine A (CsA)
CsA is a metabolite of the soil fungi Polysporium Rafti and Cylindrocarpon lucidum [16]. It potently inhibits Ca2+-dependent T-cell receptor (TCR)-mediated signal transduction leading to IL-2 production. After binding to its intracellular immunophilin receptor (cyclophilin), the drug–immunophilin complex decreases calcineurin phosphatase-dependent nuclear translocation of the cytosolic nuclear factor (NF) of activated T cells, its binding to the IL-2 enhancer and subsequent IL-2 gene
Rapamycin (sirolimus)
Rapamycin (RAPA; sirolimus) is a macrocyclic triene antibiotic produced by the actinomycete Streptomyces hygroscopicus [50]. The drug structurally resembles FK506 and binds to the same intracellular binding protein, FKBP12. RAPA-FKBP12 complexes act to inhibit the activity of the mammalian target of RAPA (mTOR) [51], [52]. This results in inhibition of multiple biochemical pathways that are critical for cytokine/ growth factor-induced cellular proliferation, ribosome synthesis, translation
Glucocorticoids (GC)
GC are potent immunosuppressive and anti-inflammatory agents used to treat autoimmune diseases and to prevent graft rejection. Their immunosuppressive actions are focused mainly on T cells and monocytes/macrophages [59]. In addition, there have been more than 50 reports to date regarding the influence of GC on DC.
Moser et al. [60] reported that GC reduced DC viability, downregulated the expression of costimulatory molecules on viable DC and strongly reduced the allostimulatory capacity of mouse
Deoxyspergualin (DSG) and its novel analogue LF15-0195 (LF)
DSG, a compound isolated from culture filtrates of Bacillus lacterosporus [95], prolongs allograft survival in rodents. Although its mechanism of action is still poorly understood, DSG has been reported to inhibit NF-κB activation and antigen processing, T or B cell differentiation and antibody production [96], [97], [98].
Thomas et al. [99] have demonstrated in rhesus macaques that simultaneous targeting of both T cells (using anti-CD3 immunotoxin) and DC (using DSG) results in renal transplant
Conclusion
Structurally diverse immunosuppressive drugs can exert strong inhibitory effects on DC maturation and function. In addition, exposure of DC to these agents results in suppressed or regulated T cell responses offering potential for manipulation of DC-T cell interactions to promote T cell unresponsiveness in a variety of clinical conditions, in particular transplantation and autoimmune disorders, but also allergic hypersensitivity.
Acknowledgements
The authors’ work is supported by National Institutes of Health grants DK49745, AI41011 and AI/DK51698.
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