This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT ALS is a progressive neurological disease which is usually fatal, causing increasing weakness and wasting of the muscles as the motor neurons of the brain and spinal cord die. This progressive deterioration eventually leads to respiratory failure due to respiratory muscle weakness. The cause of ALS is not known but recent evidence suggests that the immune system plays a significant role in the pathogenesis of ALS. In the mutant SOD1 mouse model of ALS we have documented a relative depletion of T cells, primarily T reg cells, associated with an accelerated disease progression and decreased survival. Transplantation into these mice with T reg cells slows disease progression and significantly prolongs survival. Our preliminary human ALS studies have indicated that patients that decline more rapidly have fewer T reg cells than slow progressors. The goal of this study is to increase the Treg cell population in ALS patients. The study will be conducted in collaboration with Dr. Malcolm Brenner, Chair of Cell and Gene Therapy. Dr. Brenner has carried out numerous studies using IL-2 to increase a patient''s own population of T reg cells. Patients will be given a single dose of intravenous cyclophosphamide followed by administration of IL-2, given 3 times a week for 12 weeks to repopulate the immune system with Treg cells. Each subject will be followed for one year to assess their immune response and progression of disease. This therapy has been successfully employed in minimizing graft-versus-host reactions and is an FDA-approved treatment for metastatic melanoma and kidney cancer in humans following stem cell transplantation. Although our goal is to slow disease progression and prolong survival, there is no evidence to indicate that this approach will definitely slow disease progression. However, there is presently no effective therapy for patients with ALS;and at the very least, we will enhance our understanding of the potential role of the immune system in disease pathogenesis. I. HYPOTHESIS The use of cyclophosphamide followed by a low dose IL2 administration in patients with amyotrophic lateral sclerosis (ALS) will delay disease progression for patients diagnosed with ALS. II.
SPECIFIC AIMS To assess the effects of cyclophosphamide followed by low dose IL-2 administration in patients with amyotrophic lateral sclerosis (ALS) To assess in this group of patients the safety and the toxicity of cyclophosphamide and low-dose IL-2, administered according to the dosage described in this protocol. To investigate the immunomodulatory effects of the combination of cyclophosphamide and low dose IL-2 administered in patients with ALS, by comparing before, during and after treatment: -The immunophenotype of peripheral blood mononuclear cells (PBMCs) -The suppressive activity of CD4+ CD25+ FoxP3+ Tregs -Cytokines secreted by PBMCs -NK cell analysis To measure disease progression before during and after administration of cyclophosphamide and low dose IL-2
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