Fc Receptors in tumor immunity and autoimmunity.
Inhibitory and activating FcRs are expressed jointly on myeloid effector cells and together modulate the threshold of immune complex sensitivity. Mice deficient in activating receptors are protected from antibody-mediated inflammatory responses including immune complex diseases and fail to be protected by antitumor antibodies. Conversely, mice deficient in inhibitory receptors exhibit enhanced susceptiblity to immune complex disease and are fully protected by subtherapeutic doses of antitumor antibodies. Thus Fc receptors on myeloid effector cells regulate both the protective and pathogenic consequences of cytotoxic antibodies. Using transgenic approaches we are currently identifying the FcR-bearing effector cell(s) responsible for both antibody mediated tumor protection and immune complex triggered inflammatory responses.
FcRs expressed on dendritic cells enhance antigen delivery both quantitatively and qualitatively. Immune complexes increase antigen delivery 1000-fold as compared to fluid phase pinocytosis (quantitative enhancement) and by activating ITAM-containing FcRs induce dendritic cell maturation and provide access to both class I and II antigen processing pathways (qualitative enhancement). We have shown that immune complexes are potent inducers of both class I and class II-restricted immune response in vivo and can induce both tumor immunity and DTH responses. We are investigating the immunobiology of IC-mediated antigen presentation, by identifying the regulatory roles of inhibitory and activating FcRs on dendritic cells, their contributions to antitumor antibody efficacy and are developing approaches to target FcRs for vaccine delivery. In autoimmunity states, the presence of autoantibody specific for self-antigens may enhance autoreactive T cell responses through both the exogenous pathway for CD4 responses and via cross-presentation enhance CD8 responses.
Honors and Awards
Lupus Clinical Scholar/Arthritis Investigator Award 1999
Gail Williams Biomedical Scholar Award 2000
Cancer Research Investigator Award 2000
Kimmel Scholar Award 2001
Speaker Award of the New York Academy of Sciences 2001
Charles Carrington Prize in Molecular Mechanisms of Disease 2000
Committees and Society Memberships
Arthritis Foundation Clinical immunology Study Section
DOD Army Breast Cancer Immunology Study Section
1. Rafiq K, Bergtold A, Clynes R. (2002) Immune complex-mediated antigen presentation induces tumor immunity. J Clin Invest
2. Hatzivassiliou G, Miller I, Takizawa J, Palanisamy N, Rao PH, Iida S, Tagawa S, Taniwaki M, Russo J, Neri A, Cattoretti G, Clynes R, Mendelsohn C, Chaganti RS, Dalla-Favera R. (2001) IRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells andinvolved in chromosome 1q21 abnormalities in B cell malignancy Immunity
3. Ravetch, J.V. and Clynes, R. (1998) Divergent roles of Fc receptors and complement in vivo. Annual Review of Immunology
4. Clynes, R., Dumitru, C. and J.V. Ravetch (1998) Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science
5. Clynes, R., Yoshizumi, T., Moroi, Y., Houghton, A.N., and J.V. Ravetch (1998) Fc Receptors are required for passive and active immunity to melanoma. PNAS
6. Clynes R., Maizes JS, Guinamard R, Ono M, Takai T, Ravetch JV (1999) Modulation of Immune Complex-induced Inflammation In Vivo by the Coordinate Expression of Activation and Inhibitory Fc Receptors J Exp Med