We report that OX40 stimulation drives all lineages of CD4 T cell development including Treg and the plasticity of the response is dependant on local cytokines. In TGF-β1-treated cultures, OX40 agonist increased IFN-γ and IL-4 production and diverted T cells from the Treg lineage. However, cytokine blockade in the context of OX40 stimulation promoted also enhanced Treg accumulation. This observation was evident in naive mice, as OX40 engagement enhanced Treg proliferation and accumulation in vivo. Lastly, OX40 agonist administration influenced EAE disease severity in opposing directions depending on the timing of administration. Given during Ag priming, OX40 agonist drove Treg expansion and inhibited disease, whereas, given later it enhanced T cell effector cytokine production in the CNS and exacerbated disease. Hence, OX40 signaling can augment the accumulation of all CD4 T cell lineages; however its accentuation of immune responses may have vastly different biologic outcomes depending upon the local cytokine milieu.

The KDPI system is an accurate predictor of donor contributions to transplant outcomes. Recipients of DBD kidneys experience an increase in the rate of DGF as their KDPI increases. DCD kidneys have higher DGF rates than their DBD counterparts with similar KDPIs. Patients with documented post-transplant DGF had between 3- and 5-year shorter graft half-lives when compared to recipients that did not experience DGF. Initiatives to reduce the rate of DGF could provide a significant impact on graft survival and result in a reduction in the number of patients requiring retransplant.

Ovarian hormones, including progesterone, are known to have immunomodulatory and neuroprotective effects which may alter the disease course of experimental autoimmune encephalomyelitis (EAE). In the current study, we examined the treatment potential of progesterone beginning at the onset of EAE symptoms. Progesterone treated animals showed reduced peak disease scores and cumulative disease indices, and decreased inflammatory cytokine secretion (IL-2 and IL-17). In addition, increased production of IL-10 was accompanied by increased numbers of CD19+ cells and an increase in CD8+ cells. Decreased chemokine and chemokine receptor expression in the spinal cord also contributed to decreased lesions in the spinal cord.

BackgroundRemission of multiple sclerosis during periods of high ovarian hormone secretion (such as pregnancy) has led to a great deal of interest in the potential for estrogens to treat autoimmune disease. Previous work has established that 17β-estradiol can inhibit onset of experimental autoimmune encephalomyelitis (EAE), while ethinyl estradiol (EE) can reduce the severity of established disease. In the current study, the influence of estrogen receptor-α (ERα) and the G-protein coupled estrogen receptor (GPR30 or GPER) on EE's ability to treat EAE was explored.ResultsEE reduced disease severity in wild-type and ERα knockout (ERKO) mice, but did not alter disease in the GPR30KO group. Production of anti-inflammatory IL-10 increased in EE-ERKO mice (which showed reduced disease) but not in EE-GPR30KO mice (who did not have improved disease).ConclusionsDifferential production of IL-10 following EE treatment in ERKO and GPR30KO animals may be responsible for the distinctly different effects on disease severity. Increased IL-10 in ERKO-EE compared to ERKO-Controls is likely to be an important factor in reducing established disease. The inability of EE to reduce disease in GPR30KO mice indicates an important but still undefined role for GPR30 in regulating immune reactivity.