# DEVELOPMENTAL AND GENETIC DEFECTS OF IMMUNITY

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 1994 · $182,567

## Abstract

This grant has for 25 years provided support for studies of
immunodeficient patients.  As part of this analysis, we have recently
identified 2 groups of patients with common variable immunodeficiency
(CVI), in whom abnormalities in lymphokine production appear to be a
prominent part of their immunodeficiency.  The first group (2 patients)
shows a selective deficiency of IL-2 production, the second group (4
patients) a deficiency of several lymphokines including IL-2,
interferon-gamma (IFN-gamma) and lymphotoxin.  In each case deficient
production of mRNA paralleled that for lymphokine protein. In Aim 1 of
the current application we propose to examine in depth the basis for
these defects.  We hypothesize that the most common defect will be
transcriptional.  If so, we will determine if this reflects differences
in factors acting in trans to regulate transcription of the IL-2 and for
comparison the IFN-gamma genes.  Differences in cis-regulatory sequences
are possible, but seem unlikely except in the Group 1 patients with the
deficiency restricted to IL-2 production.  If the deficiency is not due
to diminished transcription, we will explore abnormalities in mRNA
processing or stability; this seems unlikely except in the patients with
selective IL-2 deficiency.  A signal transduction defect distal to the
point which would be bypassed by calcium ionophores and PMA is considered
possible in patients with multiple lymphokine deficiencies.  This will be
inferred if a deficiency in production of multiple activation induced
trans-acting factors is found.  Attempts will be made to partially
dissect such a distal transduction defect.  To perform these analyses we
will utilize contemporary methodology, most of which is currently in
routine use in our laboratories.

Aim 2 capitalizes on another novel observation we have recently made in 2
adolescents with leukocyte adhesion deficiency.  In both cases a small
fraction of T cells express surface CD11/18 in amounts similar to
controls.  These cells have been established as long term T cell
lines/clones and propagated for up to 2 months in culture with stable
high-level expression of CD11/18.  We hypothesize that this represents a
reversion of the mutation on one allele of CD 18 (beta-chain) or an
interchromosomal crossing over resulting in a normal allele.  To test
this hypothesis we will first determine that the 8 subunit/ precursor
appear normal by immunoprecipitation of biosynthetically labeled CD11/18
+ patient cells.  If true, we will amplify by PCR and sequence the cDNA
from these patients.  The proposed studies will increase our
understanding of the immunobiology of man and permit a precise
identification of the molecular mechanisms in these patients.

## Key facts

- **NIH application ID:** 2197436
- **Project number:** 5R01HD017427-28
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **SAM.gov UEI:** HD1WMN6945W6
- **Principal Investigator:** HANS D OCHS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $182,567
- **Award type:** 5
- **Project period:** 1978-07-01 → 1995-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2197436

## Citation

> US National Institutes of Health, RePORTER application 2197436, DEVELOPMENTAL AND GENETIC DEFECTS OF IMMUNITY (5R01HD017427-28). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/2197436. Licensed CC0.

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