# GRANULOMA INITIATION FACTORS

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 1993 · $173,941

## Abstract

The long range plan of this research project is to understand the
pathomechanisms of human cutaneous hypersensitivity granulomas such as
sarcoidosis, metal induced granulomas and tuberculoid leprosy.  These
diseases create disabling, crippling conditions in patients, and because
of a lack of more precise information about the disease process, patients
do not receive optimal treatment.  This project will be carried out using
both in vivo and in vitro murine models in which macrophages aggregate
about a nidus, differentiate into epithelioid cells and organize into
tightly interdigitating cellular tubercles, closely mimicking the
clinical granulomas.  The aim is to characterize factors responsible for
these initial effects on macrophages.  A candidate 20 kD protein called
Granuloma Initiating Factor (GIF) has been purified from schistosome egg
granulomas and a potent monospecific rabbit antisera raised.  The tissue,
cellular and subcellular distribution will be sought by immuno-
histochemistry with light and microscopy, using anti-GIF IgG.  Since: a)
GIF, interleukin-1 (IL-lbeta) and tumor necrosis factor (TNF-alpha)
induce granulomatous reactions in vitro and in vivo when bound to inert
beads; and b) IL-1beta and TNF-alpha-induced in vivo granulomas contain
many GIF positive cells, macrophages grown in vitro will be examined for
he induction of GIF.  Further, the interactions between GIF and the
cytokines will be studied by use of ELISA and appropriate antibodies to
detect secreted cytokines, and by Northern blot and in situ hybridization
analysis to detect cytokine gene expression in macrophages with time
after GIF stimulation.  Also, the cytokines and other lymphokines will be
added individually to GIF-induced macrophage cultures in soluble form to
determine how they affect granuloma formation.  N-terminal eleven amino
acid sequence of GIF is identical to mouse cyclophilin and the GIF
molecule cross reacts with antisera to some mouse and human cyclophilins.
However, GIF differs from known cyclophilin, as it is concentrated in
inflammatory cells of the granulomas and not distributed ubiquitously.
In order to verify whether GIF is a cyclophilin-like, granuloma
associated protein, the gene for GIF will be cloned from a mouse cDNA
library made from mouse granuloma RNA and then expressed to produce
recombinant GIF for further biological study.

The results of studies with this novel granuloma initiating factor will
provide: a) new insights into how macrophages are induced to
differentiate into epithelioid cells and to organize into space consuming
tubercles; and b) a more logical basis for developing strategies to
interdict organized epithelioid cell granulomas in man.

## Key facts

- **NIH application ID:** 3156122
- **Project number:** 2R01AR031853-08A2
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **SAM.gov UEI:** KMH5K9V7S518
- **Principal Investigator:** WILLIAM L EPSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $173,941
- **Award type:** 2
- **Project period:** 1983-02-01 → 1996-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3156122

## Citation

> US National Institutes of Health, RePORTER application 3156122, GRANULOMA INITIATION FACTORS (2R01AR031853-08A2). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3156122. Licensed CC0.

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