Project: Research project

Project Details


In addition to controlling host sensitivity to the biological effects of
endotoxin, the Lps gene locus is an important regulator of murine macrophage
function and the immune physiology of the intact animal. Macrophages from mice
that possess the defective allele of this locus (Lpsd), exhibit a number of in
vivo abnormalities including a loss of surface receptors and poor tumoricidal
capacity. These mice also exhibit abnormal macrophage function in vivo as
manifested by their marked susceptibility to several infectious agents such as
Salmonella typhimurium. Moreover, there is a connection between these
macrophage abnormalities and endotoxin unresponsiveness since maneuvers that
increase the state of macrophage activation in vitro (T-cell lymphokines) or in
vivo (BCG infection), render Lpsd cells or mice endotoxin sensitive. In the
proposed studies, the mechanisms by which the Lps gene locus regulates
macrophage function and endotoxin responsiveness in vitro and in vivo will be
investigated. In addition, the macrophage defects caused by the Lpsd allele
will be utilized to characterize the sequence of steps involved in the
differentiation of resting monocytes to activated macrophages; to determine the
intra and inter cellular signals involved in this process, and to
physicochemically analyze and partially purify the relevant lymphokines.
Control of surface receptors for Fc and C3b will be compared in macrophages from
C3H/HeJ (Lpsd) and C3H/HeN (Lpsn) mice. T-cell derived lymphokine(s) will be
analyzed for their ability to reverse the macrophage receptor defects as well as
later parameters of activation including the ability to phagocytose particles
via C3b receptors or to respond to endotoxin. These lymphokines will then be
purified in a sequential fashion by standard column chromatographic, affinity,
and electrophoretic techniques. The role of specific cyclic nucleotides or
metabolites of arachidonic acid as inducers of macrophage differentiation will
be studied. The in vivo role of differentiated macrophages in determining
endotoxin sensitivity will be studied using the adoptive transfer of specific
cell types into endotoxin-unresponsive mice. Finally the relationship between
the observed macrophage defects and susceptibility to infection will be studied
in vivo and in vitro by analyzing the killing of gram-negative organisms.
Effective start/end date12/31/8912/31/89


  • Immunology


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