# MACROPHAGES/LYMPHOKINES IN NEONATAL HOST DEFENSES

> **NIH NIH R37** · UNIVERSITY OF WASHINGTON · 1994 · $191,842

## Abstract

The undue susceptibility of human neonates to infections with
intracellular pathogene may result in part from an intrinsic and
selective immaturity in production of IFN-gamma by neo-natal T cells and
in part from the failure of neonatal M0 to respond to IFN-gamma with
increased TNF production.  This proposal addresses the central hypothesis
that priming of T cells, which occurs by previous antigen or mitogen-
induced activation, and of M0, which occurs by exposure to IFN-gamma,
acts in part by modifying cellular signal transduction mechanisms.  Aim 1
seeks to determine if the basis for diminished IFN-gamma production, in
spite of normal interleukin 2 (IL2) production, by neonatal t cells:  1.
reflects in large part the absence of previously primed T cells with
"memory" phenotype; 2. greater production of IFN-gamma by "memory" T
cells reflects more efficient mechanisms transducing the signal to
transcribe IFN-gamma  mRNA; or 3. alternatively reflects differences in
nucleoprotein/chromatin configuration necessary for IFN-gamma
transcription.  T cells of "memory" and "non-memory" phenotype will be
identified and purified using monoclonal antibodies; we will also
determine if "memory" T cells can be derived from "non-memory" T cells by
stimulation and propagation in vitro.  Using these cells, T cell
activation induced protein phosphorylation will be studied using 2D gels
and phosphotyrosine antibodies to determine if phosphorylation occurs on
tyrosine or serine/threonine; results will be correlated with IFN gamma
production and differences in lymphocyte-specific tyrosine kinase (lck)
and protein kinase C (PKC) subtype expression and activity using specific
cDNA probes, antibodies and functional assay.  Alternatively, if
correlative differences in signal mechanisms are not confirmed, IFN-gamma
compared to IL-2 gene nucleoprotein/chromatin structure will be assessed
by DNase mapping and gel retardation assays.  Aim 2 seeks to explore, in
a manner analogous to the T cell studies, the role of enhanced/altered
signal transduction by PKC and the myeloid specific tyrosine kinases hck
and fgr in IFN-gamma enhancement of M0 TNF production.  Activation
induced protein phosphorylation and expression and activity of these
kinases will be correlated with IFN-gamma enhancement of TNF production.
If an association between increased expression/activity of a specific
kinase and IFN-gamma enhancement of TNF production is found, we will
attempt to mimic these effects by introducing into M0 cell lines
expression vectors containing that kinase(s).  The proposed studies will
dissect the lines expression vectors containing that kinase(s).  The
proposed studies will dissect the mechanisms by which IFN-gamma
production by T cells and TNF production by M0 are regulated and enhance
out understanding of the selective immaturity of these neonatal defenses.

## Key facts

- **NIH application ID:** 2197592
- **Project number:** 4R37HD018184-15
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **SAM.gov UEI:** HD1WMN6945W6
- **Principal Investigator:** Christopher B. Wilson
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $191,842
- **Award type:** 4N
- **Project period:** 1990-04-01 → 1999-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2197592

## Citation

> US National Institutes of Health, RePORTER application 2197592, MACROPHAGES/LYMPHOKINES IN NEONATAL HOST DEFENSES (4R37HD018184-15). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2197592. Licensed CC0.

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