The objective of this project is to understand how the nervous system influences the production of new B cells in the bone marrow. B cells produce antibodies following vaccination or exposure to a pathogen. The function of the immune system requires that new white blood cells (leukocytes), including B cells, be produced at controlled rates. Under or overproduction of leukocytes could lead to a reduced capacity to fight infectious disease or to leukemia, autoimmunity or other disease states. For this reason it is critical that the rate of production of leukoctyes is maintained at levels that insure sufficient numbers for their proscribed protective functions without risk of overproduction. The focus of this project is on the role of the neuropeptide calcitonin- gene related peptide (CGRP) in regulating early B cell differentiation. Cells in the immune system have CGRP receptors and CGRP influences the activity of mature lymphocytes, macrophages and granulocytes. CGRP and another sensory neuropeptide, substance P, play a role in regulating the differentiation of distinct leukocyte populations. CGRP is found in nerve endings in bone marrow, hematopoietic cells have CGRP receptors, CGRP induces production of B cell regulatory cytokines and inhibits B cell progenitor responses to IL-7.
The specific aims of this project are to show that administration of CGRP reduces the number of B cell progenitors, to identify CGRP receptor expressing cells in the B cell lineage, to examine how specific stages in early B cell development are influenced by CGRP, and to study the cellular mechanisms by which CGRP blocks B cell differentiation. The in vivo studies will determine the number of pre-B CFUs following CGRP treatment. CGRP receptor expressing cell populations will be identified by CGRP receptor mRNA analysis and by functional responses to CGRP. The role of CGRP in B cell differentiation will be studied using short term in vitro studies with cells derived from bone marrow. These studies will examine the effect of CGRP on proliferation and differentiation of distinct populations of B cell precursors present in bone marrow. Preliminary studies suggest that CGRP inhibits early B cell differentiation by cellular mechanisms involving events influenced by IL-7 and by activation of NFkappa-B. Studies will determine how CGRP inhibits NFkappa-B activation in a pre-B cell line and will examine how CGRP inhibits IL-7 responses in normal B cell progenitors. A better understanding of CGRP's role in B cell development may offer new avenues for new therapeutic approaches.
| Fernandez, Stefan; Knopf, Melissa A; Shankar, Gopi et al. (2003) Calcitonin gene-related peptide indirectly inhibits IL-7 responses in pre-B cells by induction of IL-6 and TNF-alpha in bone marrow. Cell Immunol 226:67-77 |
