| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T10191 | ||||
| Target Name | T-cell surface glycoprotein CD4 | ||||
| Target Type | Clinical Trial |
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| Action against Disease Model | TNX-355 | Hu5A8 is a molecularly engineered h uMan IgG4 antibody retaining the binding and functional properties of the murine version of 5A8 (mu5A8). This h uManized MAb has been shown to be very effective in inhibiting HIV-1 infection of h uMan CD4+ T cells and macrophages in vitro and to reduce viral load in rhesus monkeys chronically infected with simian immunodeficiency virus (SIV). | [552290] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | We used a murine liver warm IRI model to determine first whether de novo Ag-specific CD4 T cell activation was required and then what its functional mechanism was. The critical role of CD4 T cells in liver immune activation against ischemia and reperfusion (IR) was confirmed in CD4 knockout mice and CD4 depleted wild-type mice. Interestingly, the inhibition of CD4 T cell activation without target cell depletion failed to protect livers against IRI, and this suggested that T cells function in liver IRI without Ag-specific de novo activation. To dissect the T cell functional mechanism, we found that CD154 blockade, but not interferon gamma (IFN-gamma) neutralization, inhibited local immune activation and protected livers from IRI. Furthermore, agonist anti-CD40 antibodies restored liver IRI in otherwise protected CD4-deficient hosts. Finally, fluorescence-activated cell sorting analysis of liver CD4 T cells revealed the selective infiltration of effector cells, which constitutively expressed a higher level of CD154 in comparison with their peripheral counterparts. IR triggered a significant liver increase in CD40 expression but not CD154 expression, and macrophages responded to toll-like receptor 4 and type I IFN stimulation to up-regulate CD40 expression. These novel findings provide evidence that CD4 T cells function in liver IRI via CD154 without de novoAg-specific activation, and innate immunity-induced CD40 up-regulation may trigger the engagement of CD154-CD40 to facilitate tissue inflammation and injury. | [552290] | |||
| References | |||||
| Ref 552290 | Development of anti-CD4 MAb hu5A8 for treatment of HIV-1 infection: preclinical assessment in non-human primates. Toxicology. 2002 Apr 2;172(3):191-203. | ||||
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