Novel Mechanisms Of Immune Modulation By Alpha-1-Antitrypsin

Abstract

S U N D A Y 484 CD4+ and CD8+ T Cells Of Allergic Humans Express Increased Phosphorylated p38 MAP Kinase (p38MAPK), Substance P Suppresses T Cell Expression Of p38MAPK and Memory IgE Responses Bryan McCarthy, BS, Jonathan I. Silverberg, MD, PhD, MPH, Seto M. Chice, MS, Ankuri Desai, BS, Dr. Tamar A. Smith-Norowitz, PhD, Mark Stewart, MD, PhD, Dr. Rauno Joks, MD, Helen G. Durkin, PhD; Center for Allergy and Asthma Research at SUNY Downstate, Brooklyn, NY, Center for Allergy and Asthma Research, State University of New York Downstate Medical Center, Brooklyn, NY. RATIONALE: Magnetic/electrical stimulation of IgE+ human/rat left TPO cortex increases serum/blood substance P (2 hr) and CD4+/CD8+ T cell numbers (4 hr), while suppressing IgE responses (4 days). Thymus supplied T cells to blood because thymectomy or cutting of spinal cord at T2 (thymic innervation level) abrogated their appearance. Substance P suppresses specific murine IgE responses in vivo/vitro, and a relationship between p38MAPK and IL-4 has been reported. The effect of substance P on p38MAPK expression by human lymphocyte subsets and memory IgE responses has not been studied. METHODS: Distributions of p38MAPK+ lymphocytes (CD4+,CD8+,CD19+,CD16+) in PBMC obtained from ragweed sensitized IgE+ humans were determined6 15-30 min incubation with PMA6 substance P (flow cytometry). In addition, PBMC were cultured for 0-12 days 6 ragweed antigen 6 substance P and IgE levels in supernatants determined (ELISA). RESULTS: Before PMA stimulation, virtually no p38MAPK+ T cells (CD4+, CD8+), B or NK cells were detected in PBMC (<5%). After PMA, virtually all T cells, and CD4+ T cells which had been purified from PBMC, were p38MAPK+ (90-98%), with no change in p38MAPK+ B or NK cells.When PBMCor purified CD4+ T cells were incubatedwith PMA + substance P, p38MAPK+ CD4+ and CD8+ T cell numbers were suppressed (50-75%) When PBMC were cultured with ragweed antigen, peak IgE responses were induced on day 8; inclusion of substance P in culture prevented induction of these responses on all days. CONCLUSIONS: Taken together, our results indicate that brain can suppress IgE responses by releasing substance P.