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Objectives: Apoptosis plays an important role in the progression of the ischemic penumbra after reperfusion. Estrogen and progesterone have neuroprotective effects against ischemic brain damage, however the exact mechanisms of neuroprotection and signaling pathways is not completely understood. In this study, we investigated the possible regulatory effects of a combined steroid treatment on extrinsic and intrinsic apoptotic signaling pathways after cerebral ischemia. Methods: Adult male Wistar rats were subjected to transient middle cerebral artery occlusion (tMCAO) using an intraluminal filament technique for 1 h followed by 23 h reperfusion. Estrogen and progesterone were immediately injected after tMCAO subcutaneously. Sensorimotor functional tests and the infarct volume were evaluated 24 h after ischemia. Protein expression of calpain-1 and Fas receptor (FasR), key members of intrinsic and extrinsic apoptosis, were determined in the penumbra region of the ischemic brain using western blot analysis, immunohistochemistry, and TUNEL staining. Results: Neurological deficits and infarct volume were significantly reduced following hormone therapy. Calpain-1 up-regulation and caspase-3 activation were apparent 24 h after ischemia in the peri-infarct area of the cerebral cortex. Steroid hormone treatment reduced infarct pathology and attenuated the induction of both proteases. FasR protein levels were not affected by ischemia and hormone application. Conclusion: We conclude that a combined steroid treatment inhibits ischemia-induced neuronal apoptosis through the regulation of intrinsic pathways. [ABSTRACT FROM AUTHOR]

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological and clinical similarities to the major human demyelinating disease multiple sclerosis (MS). Multiple lines of evidence in recent years implicate the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) in the pathogenesis of both EAE and MS. TNF-α cellular responses are mediated by signaling through receptors, which are expressed in two functional forms, designated according to molecular weight p55/60 and p75/80. We report a treatment trial using the extracellular domain of the p80 TNFR in a bivalent fusion construct designated soluble tumor necrosis factor receptor (sTNFR):Fc to treat EAE. sTNFR:Fc/p80, given after the onset of clinical signs, reduced the clinical deficit of the first attack of relapsing-remitting EAE ( RR-EAE ) and the exacerbation rate for subsequent attacks. The effect was reversible as mice treated with sTNFR:Fc/p80 reverted to an exacerbation rate and disease severity typical of placebo-treated animals after treatment was discontinued. Treatment of RR-EAE with sTNFR:Fc/p80 decreased expression of chemokines MIP-1α (Monocyte Inflammatory Protein)/CCL3, MIP-1β/CCL4 and MIP-2/CXCL1-2 in the central nervous system. This treatment trial reveals an important function of TNF in the pathogenesis of RR-EAE and propose the mechanism of beneficial action of sTNFR:Fc/p80 in this disease. [ABSTRACT FROM AUTHOR]

Mice genetically deficient in TGF-β1 or TGF-β signaling c apacity in T or B cells demonstrate profound immune dysregulation, as evidenced by increased lymph node size, expression of markers o f memory/activation on T cells, inflammation in a variety of tissues and development of autoantibodies. H owever, this constant and complete lack of TGF-β1 or TGF-βR signaling may not reflect effects of TGF-β neutralization using antibodies in mature animals. Thus, t he present studies were designed to determine if administration o f an anti-TGF-β monoclonal antibody (neutralizes TGF-β1, 2 and 3) to mature, normal mice results in evidence of immune dysregulation or immune-mediated pathology. An initial study examined daily administration of 0.25, 0 .75 and 2.5 mg/kg of anti-TGF-β to mice for three weeks, achieving blood levels of as high a s 9 mg/ml. Comprehensive hematological and histopathological evaluation showed no evidence of pathology. A second study was designed to extend the antibody treatment period and further examine t he functional status of the immune system. Mice were injected with 1 mg/mouse ( approximately 5 0 m g/kg) o f anti-TGF-β (1D11) three times per week achieving circulating blood levels of 1-2 mg/ml. Many parameters of immune status were assessed, including natural killer ( NK) c ell activity, lymphocyte proliferative responses, phagocytic activity, phenotypic assessment of leukocyte subsets, and serum measurements of proinflammatory cytokines, autoantibodies and immunoglobulin isotypes. In addition, histopathological assessment of heart, lungs, liver, kidney, salivary glands, skin, spleen and lymph nodes was also performed. Very few of the multiple immune parameters examined showed detectable changes in anti-TGF-β-treated mice. Changes that were observed were primarily restricted to the spleen and included increased spleen cell r ecoveries, increased percentages of macrophages, decreased... [ABSTRACT FROM AUTHOR]

Gamma delta (γδ) T cells are the all-rounders of our immune-system with their major histocompatibility complex-unrestricted cytotoxicity, capacity to secrete immunosti-mulatory cytokines and ability to promote the generation of tumor antigen-specific CD8+and CD4+T cell responses. Dendritic cell (DC)-based vaccine therapy has the prospective to harness these unique features of the γδ T cells in the fight against cancer. In this review, we will discuss our current knowledge on DC-mediated γδ T cell activation and related opportunities for tumor immunologists. [ABSTRACT FROM PUBLISHER]

The CD8+T-cell response comprises terminally differentiated effector cells and antigen-experienced memory T cells. The latter encompass central (TCM) and effector (TEM) memory cells. TCMcells are superior in their protection against viral and bacterial challenges and mediation of antitumor immunity due to their higher proliferative ability upon antigen re-encounter. Defining a mechanism to enhance TCMcells and delay terminal differentiation of CD8+T cells is crucial for cancer immune therapy, as it can promote a better tumor immune response. The differentiation of CD8+memory T cells is thought to be coordinated by the phosphoinositide 3-kinase (PI3K)/Akt pathway. We, therefore, investigated the role of Akt isoforms in the differentiation and proliferation of memory CD8+T cells. We found that Akt1 and Akt2, but not Akt3, drive the terminal differentiation of CD8+T cells, and their inhibition enhances the therapeutically superior TCMphenotype. Furthermore, the inhibition of Akt1 and Akt2, but not Akt 3, delays CD8+T-cell exhaustion and preserves naïve and TCMCD8+T cells, thus enhancing their proliferative ability and survival and prolonging their cytokine and Granzyme B production ability. Here, we define a mechanism in which proliferative potential, function, and survival of CD8+T cells are enhanced by maintaining a reservoir of TCMand naïve cells using only Akt1 and Akt2 inhibition. Therefore, our findings strongly suggest the utility of using Akt1 and Akt2 inhibitors to modulate CD8+T cells, both for adoptive cell transfer and vaccine-based cancer immune therapies. [ABSTRACT FROM AUTHOR]