Peripheral Immune Cell Functionality in Amyotrophic Lateral Sclerosis (P03.184)

Abstract

Objective: To investigate the functionality of circulating immune cells in ALS patients. Background Amyotrophic lateral sclerosis (ALS) axonal pathology precedes motoneuron degeneration during disease progression in patients and the mSOD1 mouse model. We and others have shown that a functional immune system is neuroprotective in mSOD1 mice, enhancing survival and promoting facial motoneuron (FMN) survival levels after axotomy. Increased levels of FMN loss after axotomy were seen in immunodeficient mice, but wildtype levels of FMN survival could be restored by adoptively transferring wildtype splenocytes or CD4+ T cells prior to axotomy. Interestingly, the adoptive transfer of mSOD1 whole splenocytes did not rescue axotomy-induced FMN death in immunodeficient mice, but isolated CD4 + T cells (from the splenocyte population) effectively mediated neuroprotection to similar levels as wildtype CD4 + T cells, suggesting that the defect in immune neuroprotection was NOT explained by a functional defect in CD4 + T cells. Previous studies examining the peripheral immune compartment in ALS patients have yielded varied results regarding levels/function of CD4 + T cells. Based on the results above, we hypothesize that the peripheral immune microenvironment in ALS activates CD4 + T cells early on, but the neuroprotective effects of certain T cell subsets are subsequently inhibited by non-Tcell components of the immune system. Design/Methods: In vitro T cell proliferation assays were utilized to assess the function of ALS T cell subsets activated with anti-CD3 stimulation and compared to controls. Results: ALS CD4 + T cell subsets maintain their functional and proliferative capabilities when removed from the ALS microenvironment and activated polyclonally. No differences in T regulatory cell function or FoxP3 expression were detected in ALS samples compared to controls. Conclusions: ALS CD4 + T cells function normally in response to polyclonal stimulation in vitro , suggesting that other components of the ALS immune system (B cells, dendritic cells, or macrophages) underlie the defect in neuroprotective CD4 + T cell functionality. Supported by: The ALS Association (JR). Disclosure: Dr. Mesnard has nothing to disclose. Dr. Muthusamy has nothing to disclose. Dr. Xin has nothing to disclose. Dr. Sheng has nothing to disclose. Dr. Jones has received research support from Veterans Affairs, the National Institutes of Health, and the Les Turneer ALS Foundation. Dr. Prabhakar has received personal compensation for activities with Gliknik Inc. as a consultant.Dr. Prabhakar has received research support from NIH. Dr. Rowin has nothing to disclose. Dr. Meriggioli has received personal compensation for activities with Athena Diagnostics, Talecris Biotherapeutics, Gliknik, and Celegene Corporation. Dr. Meriggioli receives patent payments for a patent on bispecific antibody coated dendritic cells. Dr. Meriggioli has received research support from the NIH/NINDS and the Muscular Dystrophy Association.