# MECHANISMS OF COMPLEMENT ACTIVATION AND CONTROL

> **NIH NIH R01** · SCRIPPS CLINIC AND RESEARCH FOUNDATION · 1988 · $218,621

## Abstract

This research project includes an investigation of the
physiological mechanisms regulating the activation and control of
human complement.  We will investigate the C3b- and C4b-
mediated inhibition of immune complex-inducer C1 activation.
The effects of factors H, I and C4b-binding protein on this
feedback inhibition will be assessed.  We will determine if the
covalent binding of nascent C3b and C4b to antibody, antigen or
other  complement proteins is crucial.  The effect of antibody
subclass on the strength of feedback inhibition will be studied.
Are nonimmune activators of C1 also inhibited by nascent C3b
and C4b?  We will also determine if feedback inhibition correlates
with antibody-antigen dissociation.  The inhibiting properties of
the C4A isotype of C4 will be compared with the C4B isotype in
order to gain insight as to the chemical group to which the
inhibiting molecules bind.  (C4A prefers binding to amino groups,
while C4B prefers hydroxyl groups).  If, as preliminary data
suggest, immunoglobulin is the receptor molecule for the
inhibiting complement protein(s), we will then selectively modify
different amino acids (or carbohydrate) of the immunoglobulin.
The goal is to block the C3b and/or C4b binding site(s) without
affecting the complementing activating or antigen binding
activities.  (If C1q turns out to be the receptor molecule, it will
be similarly treated.) An antibody that is successfully modified
(i.e., so that it is not subject to feedback inhibition by C3b and
C4b) would be a potent complement activator, able to generate
high levels of biologically active mediators upon binding to
antigen.  This modified antibody might be of great practical use
for monoclonal antibody therapy.

We will also study the effects of cellular-derived protease
inhibitors (termed protease nexin or PN) on complement
activation.  PN-I will be isolated from cultured fibroblasts and
characterized as to its ability to inhibit activated C1, the fluid
phase activation of C1 and immune complex-induced activation of
C1.  Comparisons will be made with the plasma protein C1-
inhibitor.  Furthermore, quantitative and qualitative comparisons
will be made between fibroblasts derived from normal individuals
vs. those with hereditary angioedema (HAE), a disease
characterized by a genetic deficiency in C1-inhibitor function.
Since the pathological processes leading to edema may be also
occurring outside the blood vessel, these studies are relevant for a
better understanding of the disease.

## Key facts

- **NIH application ID:** 3125775
- **Project number:** 5R01AI014502-11
- **Recipient organization:** SCRIPPS CLINIC AND RESEARCH FOUNDATION
- **Principal Investigator:** ROBERT J ZICCARDI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1988
- **Award amount:** $218,621
- **Award type:** 5
- **Project period:** 1978-01-01 → 1990-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3125775

## Citation

> US National Institutes of Health, RePORTER application 3125775, MECHANISMS OF COMPLEMENT ACTIVATION AND CONTROL (5R01AI014502-11). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3125775. Licensed CC0.

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