R01AI165513

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 C5a receptor (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.

Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Cleveland, Ohio 44195 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 400% from $625,596 to $3,127,980.