Drugs which Inhibit DC Maturation and/or Function

A diverse variety of pharmacologic agents have been shown to inhibit DC maturation and to promote their tolerogenicity.

• Acetylsalicylic acid (Aspirin;) Although asprin has been shown not to block , the drug has an inhibitory action on DC maturation. Aspirin reduces CD40, CD80, CD86, and MHC class II expression on the DC surface. Aspirin also enhances the endocytic capacity of DC. Moreover, aspirin-treated D and impairs IL-12 production. Aspirin exerts its effect by suppressing NF-kB translocation, which is of pivotal importance for DC maturation. Asprin treated DC also fail to induce a normal cell-mediated immune response. This can be seen where a s.c. injection of TNBS pulsed DC induce a strong contact hypersensitivity response in mice after rechallenge of the animals with the model hapten 7 days later whereas the responses of animals sensitized with TNBS-pulsed aspirin treated DC are similar to those of unsensitized animals. 
• cortisosteroids also suppress NF-kB and also induce the generation of IL-5 and IL-10 secreting cells over those that produce IFNy, thus favoring immune deviation toward T helper type 2 responses.
• vitamin D3 and analogs: A number of studies has clearly demonstrated that 1,25(OH)2D3, the activated form of Vitamin D inhibit the differentiation and maturation of DCs. These studies, performed either on monocyte-derived DCs from human periopheral blood or on bone marrow derived mouse DCs, have consistently shown that in vitro treatment of DCs with D3 and its analogues leads to downregulated expression of the costimulatory molecules CD40, CD80, CD86 and to decreased IL-12 and enhanced IL-10 production, resulting in decreased T cell activation. Vitamin D3 treated DC not only fail to activate T cells but also induce a T cell hyporespondsiveness to further stimulation with mature DC. 

The prevention of DC differentiation and maturation as well as the modulation of their activation and survival leading to DCs with tolerogenic phenotype and function play an important role in the immunoregulatory activity of D3. In vivo studies have that pretreatment with vitamin D3 donor DC prolonged skin allograft surfival in mice. Tolerogenic DCs induced by a short treatment with D3 are probably responsible for the capacity of this hormone to induce  that are able to mediate transplantation tolerance. 

• Tacrolimus are calcineurin inhbitiros (CsAs). Tacrolimus has no effect on DC differentation and no effect on DC maturation but has an inhibitory action on DC functions. It inhibits the allostimulatory capacity of DC as determined by ascertaining their capacity to induce 3H-thymidine incorporation into purified naive alloegenic T cells in a mixed lymphoctye reaction. The mechanisms of CsA and tacrolimus are well known for T lymphocytes in that they inhibit the activity of calcineurin, an enzyme that stimulates many transcription factors involved in the synthesis of cytokines like IL-2 and IFN-y. In the case of DC, the mechanisms of action of CsAs are not known.
• • Desoxyspergualin (DSG) is known to inhibit NF-kB through inhibitory effects on the molecular chaperon heat shock protein 70. Studies undertaken with this agent have demonstrated inhibition of rhesus macaque DC maturation. The cells exposed to DSG exhibit a decrease in NHC class II and CD83 expression. The endocytosis of treated cells is greater than in control DC, consistent with DC immaturity. Coupled with the inhibition of maturation, DSG DC have impaired antigen-presenting functions, when by reduced stimulatory activity in allogeneic MLR cultures. Moreover, treated DC express low levels of  suggesting that DSG may also have an inhbitory effect on DC migration in vivo.
  • CsA: promotes the rapid disappearance of DCs fromt he thymus. As CsA does not inhibit DC differentaiton or markedly promote DC death, it is possible that this relates to interference of CsA with DC migration. Additionally, CsA has been reported to inhibit the expression of cyclooxygenase 2 (COX2) by DCs, a key enzyme involved in the production of proostaglandin E2(PGE2) which is an important inducer of DC migration and has been suggested to mediate its effect by coupling CCR7 to its signal tranduction modules. 

  Inhibition of Signalling Pathways 

  Inhibition of p38 blocks DC maturation and cytokine production, when induced either by cytokines or by TLR ligands. A molecular mechanism for this effect has been proposed, by which p38 activation leads to chromatin rearrangement and hence enhances accessibility for transcription factors to locate theri binding sites within relevant promoters.