IL2 DEFICIENCY MEDIATES AUTOIMMUNITY IN MRL-LPR MICE

许多自身免疫诱导模型需要增强免疫

Many induced models of autoimmunity necessitate augmenting the immune response to a specific target tissue. In distinction, several naturally arising mouse models of systemic lupus erythematosus (SLE) manifest hyporesponsive T lymphocyte responses, particularly regarding deficient IL2 production. This is strikingly present in the MRL-lpr mouse. These mice develop an SLE diathesis accompanied by an enormous accumulation of abnormal TCR-alphBeta+ CD2- B220- B220+ CD4-CD-8 T cells that produce negligible IL2 when activated and as a result, manifest little proliferative capacity. A such they resemble anergic T cells and other CD2-T cells. The lpr defect results form a mutation of the fas gene which mediates apoptosis. This may account for the pronounced accumulation of T cells, but does not readily explain the developmental arrest of these cells, nor the reason for the defect in signal transduction and hence IL2 production. This proposal will examine this defect at the level of the IL2 gene regulatory transcription factors. It will then assess the potential benefits of IL2 in vivo therapy in MRL- lpr mice and monitor the alterations in T cell phenotype and function that may be responsible for this. The first specific aim analyzes the expression of the IL2 gene regulatory transcription factors by gel mobility shift in fresh and cultured MRL-lpr CD4-8-, CD4+, and MRL+/+ T cells before and after activation with PMA and ionomycin, or anti-CD3 mAb. This will be compared to T cells stimulated with anti-CD3 mAb in the absence or presence of anti-fas mAb. This portion will define the nature of the IL2 defect in lpr CD4-8-T cells and help establish the contribution if fas in costimulation of IL2 production. The second specific aim will extend the preliminary in vitro observation that IL2 can induce cell cycling, CD2 induction, B220 loss, and gain of function by lpr CD4-8- T cells. MRL-lpr mice will be administered IL2 in vivo as a cDNA construct, as the phenotype and function of the CD4-9- monitored while the potential beneficial or detrimental effects on the autoimmune process are determined.