Antibodies regulate immune responses, not only by recognition of foreign agents but also through the modulation of effector cell function. This latte action is mediated through binding of the antibody constant region, the Fc region, to cell surface receptors. Fc receptors (FcRs), which are expressed by diverse populations of immune cells, can be grouped based on the antibody class they bind. The receptors that bind IgG antibodies, the Fc? receptors, represent the largest family and are of particular interest because antibody binding can either stimulate or attenuate the immune response, depending on the receptor activated. Understanding the function of these receptors and the variation between individuals in their structure and expression is important, not only because of their ability to regulate immune responses, but also because of the increased therapeutic use of therapeutic antibodies, especially in the treatment of cancer. Species differences in the mouse and human have hampered the use of the mouse in translational studies examining the engagement of these receptors by therapeutic human antibodies. In addition, these differences have limited the ability to examine the impact of polymorphisms in these receptors on the pathogenesis of immune diseases and on the responsiveness of patients to therapeutic antibodies. To address this problem we propose to generate a mouse line which expresses the low affinity family of human FCGR genes in place of the endogenous mouse genes. These lines will be easy to breed and thus will be appropriate not only for basic research studies, but also for preclinical evaluation o new therapeutic antibodies.

Public Health Relevance

In this application we propose to generate mouse models useful for the testing of therapeutic antibodies developed for the treatment of cancer and other diseases. Studies have shown that the effectives of anti-tumor antibodies can vary between individuals depending on polymorphism in genes encoding the Fc IgG receptors. These are receptors that bind the constant region of antibodies. The engagement of these receptors by IgG complexes likely enhances killing of tumor cells by the immune system. The mice we propose to generate will also be useful for studying the contribution of these polymorphisms to other disease such as lupus (Systemic lupus erythematosus).

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21OD012234-01A1
Application #
8638425
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mirochnitchenko, Oleg
Project Start
2014-04-01
Project End
2016-01-31
Budget Start
2014-04-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$228,000
Indirect Cost
$78,000
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599