# PROTEASE CONTROL OF LYMPHOCYTE-MEDIATED CYSTOLYSIS

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 1989 · $120,366

## Abstract

This proposal explores the hypothesis that serine proteases have a
key role in lymphocyte-mediated lysis.  Three lines of evidence
support this concept: 1) inclusion of protease inhibitors in NK and
T cell assays blocks killing; 2) lymphocytes have proteases in their
cytotoxic granules; and 3) genes for three different proteases are
preferentially expressed by cytotoxic lymphocytes.  Even though
protease and cytolytic proteins are both found in high density
cytoplasmic granules of lymphocytes, a function for the granule
proteases has not been demonstrated by other investigators.

Several discoveries from the Hudig laboratory reconcile the other
data and indicate that the proteases do function in cytotoxicity.
Very reactive protease inhibitors block granule-mediated lysis,
whereas less reactive inhibitors do not.  With more sensitive
substrates, they have found that there are chymotrysin-like
proteases (chymases) as well as trysin-like proteases (tryptases) in
the cytotoxic granules.  When the proteases are inhibited,
granule-mediated lysis is either delayed or completely inhibited.
Their data also indicate that the protoeases may have important
functions in the processing of granule proteins and that these
functions occur prematurely during standard preparation of
cytotoxic granules  Inclusion of selected protease inhibitors in the
preparation of granules can arrest cleavage of large proteins and
block subsequent cytotoxicity.

In this grant, they will purify and characterize the chymases and
tryptases.  Next they will determine which proteases are
important to lysis using purified proteases to restore cytolytic
activity to inhibited granules.  Then they will identify the natural
substrates of these proteases.  These studies should indicate the
first functional role for any chymase and elucidate a new serine
protease cascade that initiates lymphocyte-mediated lysis.
Control of this cascade could prevent acute graft rejection and
other immunopathological phenomena that are mediated by
cytotoxic lymphocytes.

## Key facts

- **NIH application ID:** 3177453
- **Project number:** 5R01CA038942-05
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **SAM.gov UEI:** WLDGTNCFFJZ3
- **Principal Investigator:** Dorothy Hudig
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $120,366
- **Award type:** 5
- **Project period:** 1984-05-11 → 1990-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3177453

## Citation

> US National Institutes of Health, RePORTER application 3177453, PROTEASE CONTROL OF LYMPHOCYTE-MEDIATED CYSTOLYSIS (5R01CA038942-05). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3177453. Licensed CC0.

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