Complement regulates macrophage and platelet function in kidney transplants

ABSTRACT
The potential for complement activation during organ recovery, ischemia reperfusion and antibody-mediated
rejection (AMR) is well-recognized. As a result, numerous therapeutic inhibitors of complement have been
developed and tested in the treatment of AMR. Inhibitors of the terminal complement component C5, and more
recently, C1 the first component of the classical pathway have been tested most extensively. Extensive evidence
indicates C1q functions as a pattern recognition receptor (PRR) that binds apoptotic cells and mediates a non-
inflammatory clearance by macrophages. In fact, C1q deficient patients and mice do not clear apoptotic cells
efficiently and develop florid autoimmunity. Remarkably little is known about the effects of C1q in transplantation.
However, in recent clinical trials, injury caused by delayed graft function has been diminished by treatment with
C1 inhibitor (C1inh), a serine protease inhibitor that terminates complement activation, but leaves C1q intact.
These results invite the obvious question: Does C1inh work because it truncates the complement cascade and
decreases production of downstream inflammatory mediators or does C1inh work because it leaves C1q intact
to modulate macrophages and cells that express C1q receptors? Of course, these are not mutually exclusive.
More is known about the functions of C5a in antibody induced inflammation. C5a is a potent chemoattractant
and activator of neutrophils and macrophages. However, platelets also express C5aR. We have demonstrated
that platelets accumulate within minutes after antibody binds and activates complement on graft endothelium.
We propose the hypothesis that C1q down modulates whereas C5a upregulates inflammatory responses in
transplants; therefore preserving C1q functions and inhibiting C5a functions will decrease AMR. We will test this
hypothesis in the following 3 specific aims: 1) Test the capacity of C1q to function as a PRR to remove potentially
immunogenic extracellular vesicles during reperfusion after transplantation and decrease the induction of allo-
and autoantibody responses. 2) Test the effects of C5a on neutrophil and macrophage functions in ischemia-
reperfusion and chronic AMR. 3) Test the effects of C5a on platelet functions in acute and chronic AMR. These
specific aims encompass and enhance common threads of our PPG that focuses on mechanisms underlying
AMR. The goal of this proposal is to provide the basis for rational therapeutic enhancement of the beneficial
functions of C1q in transplants and modulation of proinflammatory effects of C3a and C5a.

Grant Number: 5R01AI165513-05
NIH Institute/Center: NIH
Principal Investigator: William Baldwin