Selective inhibition of T cell costimulation using the B7-specific fusion protein CTLA4-Ig has been shown to induce long-term allograft survival in rodents. Antibodies preventing the interaction between CD40 and its T cell-based ligand CD154 (CD40L) have been shown in rodents to act synergistically with CTLA4-Ig. It has thus been hypothesized that these agents might be capable of inducing long-term acceptance of allografted tissues in primates. To test this hypothesis in a relevant preclinical model, CTLA4-Ig and the CD40L-specific monoclonal antibody 5C8 were tested in rhesus monkeys. Both agents effectively inhibited rhesus mixed lymphocyte reactions, but the combination was 100 times more effective than either drug alone. Renal allografts were transplanted into nephectomized rhesus monkeys shown to be disparate at major histocompatibility complex class I and class II loci. Control animals rejected in 5-8 days. Brief induction doses of CTLA4-Ig or 5C8 alone significantly prolonged rejection-free survival (20-98 days). Two of four animals treated with both agents experienced extended (>150 days) rejection-free allograft survival. Two animals treated with 5C8 alone and one animal treated with both 5C8 and CTLA4-Ig experienced late, biopsy-proven rejection, but a repeat course of their induction regimen successfully restored normal graft function. Neither drug affected peripheral T cell or B cell counts. There were no clinically evident side effects or rejections during treatment. We conclude that CTLA4-Ig and 5C8 can both prevent and reverse acute allograft rejection, significantly prolonging the survival of major histocompatibility complex-mismatched renal allografts in primates without the need for chronic immunosuppression.Unmodified organ transplantation between genetically nonidentical individuals invariably results in immunological rejection of the organ through T cell-dependent mechanisms. Successful transplantation of allogeneic organs has therefore required the administration of drugs directed at suppressing recipient T cell function. Both calcineurin phosphatase inhibitors and glucocorticosteroids are used clinically, and both prevent the T cell-mediated release of activating cytokines, particularly IL-2. Therapy with these agents is imperfect, however. Both act by impairing T cell antigen receptor (TCR) signal transduction, the sole mediator of T cell antigen recognition, thus minimizing the potential for specific immune interaction between the recipient and donor. They also act on all T cells indiscriminately. In addition, the effect of these drugs is not lasting, such that cessation of immunosuppression has generally resulted in graft loss even after prolonged rejection-free survival. Thus, transplant patients are required to suffer the consequences of nonspecific immunosuppression to avoid rejection. These consequences include an increased risk to the patient of infection and malignancy as well as significant drug related expense and toxicity.Data establishing that T cell activation require...
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.
Campath-1H, an anti-CD52 monoclonal antibody, was used as induction therapy (40 mg i.v. total dose) in 29 primary human renal transplants, and the patients were maintained on rapamycin monotherapy (levels 8-15 ng/mL) post-transplant. Campath-1H profoundly depletes lymphocytes long-term and more transiently depletes B cells and monocytes. All patients are alive and well at 3-29 months of follow up. One graft was lost because of rejection. There have been no systemic infections and no malignancies. Eight of 29 patients have experienced rejection, which was successfully treated in seven of eight patients. Five of these patients had pathological evidence of a humoral component of their rejection. Seven of the 29 patients were converted to standard triple therapy on account of rejection. Rapamycin was generally well tolerated in that there were no significant wound-healing problems; two lymphoceles required surgical drainage; and most patients were treated with a lipid-lowering agent. Flow crossmatch testing post-transplant revealed evidence of alloantibody in two patients tested with previous combined cellular and humoral rejection. Biopsies have shown no chronic allograft nephropathy to date. In view of the relatively high incidence of early humoral rejection, we plan to modify the immunosuppressive regimen in subsequent pilot studies. This clinical trial provides insight into the use of Campath-1H induction in combination with rapamycin maintenance monotherapy.
Lung diseases, including asthma, COPD, and other autoimmune lung pathologies are aggravated by exposure to particulate matter (PM) found in air pollution. IL-17 has been shown to exacerbate airway disease in animal models. As PM is known to contain aryl hydrocarbon receptor (AHR) ligands and the AHR has recently been shown to play a role in differentiation of Th17 T cells, the aim of this study was to determine whether exposure to PM could impact Th17 polarization in an AHR-dependent manner. This study used both cell culture techniques and in vivo exposure in mice to examine the response of T cells to PM. Initially experiments were conducted with urban dust particles from a standard reference material, and ultimately repeated with freshly collected samples of diesel exhaust and cigarette smoke. The readout for the assays was increased T cell differentiation as indicated by increased generation of IL-17A in culture, and increased populations of IL-17 producing cells by intracellular flow cytometry. The data illustrate that Th17 polarization was significantly enhanced by addition of urban dust in a dose dependent fashion in cultures of wild-type but not AHR-/- mice. The data further suggest that polycyclic aromatic hydrocarbons played a primary role in this enhancement. There was both an increase of Th17 cell differentiation, and also an increase in the amount of IL-17 secreted by the cells. In summary, this paper identifies a novel mechanism whereby PM can directly act on the AHR in T cells, leading to enhanced Th17 differentiation. Further understanding of the molecular mechanisms responsible for pathologic Th17 differentiation and autoimmunity seen after exposure to pollution will allow direct targeting of proteins involved in AHR activation and function for treatment of PM exposures.
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