CD154 is the ligand for the receptor CD40. This ligand-receptor pair mediates endothelial and antigen-presenting cell activation, and facilitates the interaction of these cells with T cells and platelets. We demonstrate here that administration of a CD154-specific monoclonal antibody (hu5C8) allows for renal allotransplantation in outbred, MHC-mismatched rhesus monkeys without acute rejection. The effect persisted for more than 10 months after therapy termination, and no additional drug was required to achieve extended graft survival. Indeed, the use of tacrolimus or chronic steroids seemed to antagonize the anti-rejection effect. Monkeys treated with antibody against CD154 remained healthy during and after therapy. The mechanism of action does not require global depletion of T or B cells. Long-term survivors lost their mixed lymphocyte reactivity in a donor-specific manner, but still formed donor-specific antibody and generated T cells that infiltrated the grafted organ without any obvious effect on graft function. Thus, therapy with antibody against CD154 is a promising agent for clinical use in human allotransplantation.

Since both the nature and the amplitude of an antigen-specific T cell response are dependent on co-stimulatory signals, we have investigated the role of CD28/CD152-mediated T cell co-stimulation in the regulation of experimental cutaneous leishmaniasis. CD28-deficient mice and their wild-type littermates are equally susceptible to Leishmania major infection. Whole anti-CD152 antibody significantly exacerbates the disease while anti-CD152 Fab ameliorates the disease in genetically susceptible BALB/c mice but not in C57BL/6, a resistant strain. The anti-CD152-induced exacerbation of the disease is accompanied by increased IL-4-secreting cell number, diminished parasite-specific delayed-type hypersensitivity (DTH) response and augmented anti-2,4,6-trinitrophenyl (TNP) IgG1 in response to TNP-leishmanial antigen crude soluble antigen (CSA), suggesting an exaggerated Th2 type of response. Anti-CD152 Fab-mediated amelioration of the disease is associated with increased IFN-gamma-secreting cell number, increased parasite-specific DTH response and enhanced IgG2a isotype in response to TNP-CSA suggesting a Th1 type of response. Unlike TNP-CSA, TNP-keyhole limpet hemocyanin does not induce the change in Ig isotype, indicating that the immunomodulatory effect of anti-CD152 is antigen specific. Anti-CD152 antibody-induced early change in Th subsets suggests an important role for CD152 in determining the course of L. major infection, perhaps by alteration of Th subset differentiation.

Although enhanced monocytopoiesis is a hallmark of leishmaniasis, its significance in determining the course of the disease has not been addressed. While the number of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)‐secreting cells increases in the draining lymph nodes in a resistant mouse strain (C57BL/6) during disease, in a susceptible strain (BALB/c) the number of interleukin‐3 (IL‐3)‐secreting cells increases. Treatment of BALB/c mice with anti‐IL‐3 antibody significantly reduces the disease score. Bone marrow macrophages derived under stimulation with IL‐3 (IL‐3‐Mϕ) or GM‐CSF (GM‐Mϕ) differ functionally. GM‐Mϕ are significantly more responsive to IFN‐γ‐induced augmentation and more refractory to IL‐4‐mediated suppression of anti‐leishmanial activity than IL‐3‐Mϕ. LPS‐induced IL‐12 and TNF‐α secretion by both the susceptible and resistant strain‐derived macrophage subsets are down‐regulated. Despite down‐regulation of IL‐12 secretion, GM‐Mϕ favor expansion of IFN‐γ‐secreting cells and IL‐3‐Mϕ favor IL‐6‐dependent expansion of the IL‐4‐secreting Th subset. Adoptive transfer of leishmanial antigen‐pulsed IL‐3‐Mϕ and GM‐Mϕ prior to infection either aggravated or reduced the disease score, respectively, in BALB/c mice. Anti‐IL‐6 treatment reverted the Th subset profile not only in vitro but also in vivo, resulting in a reduced disease score in both infected BALB/c mice and IL‐3‐Mϕ recipients. The disease score in IL‐3‐Mϕ recipients is also reduced significantly after anti‐IL‐4 treatment.

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