Deficiency of Transmembrane Protein VISTA (V-domain Immunoglobulin Suppressor of T-cell Activation) Ameliorates Murine Collagen-II Antibody-Induced Arthritis

Roy Fava^1,2, Sabrina Ceeraz³, Susan Eszterhas⁴, Petra Sergent³, Christopher Burns⁵ and Mathew Vincenti^6,7, ¹Research, Department of Veterans Affairs, White River Junction, VT, ²Department of Medicinee, Geisel School of Medicine at Dartmouth, Lebanon, NH, ³Microbiology/Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH, ⁴Research, Department of Veterans Affairs, white River Junction, VT, ⁵Section of Rheumatology, Geisel School of Medicine at Dartmouth, Lebanon, NH, ⁶Department of Veterans Affairs, White River Junction, VT, ⁷Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, NH

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: complement, immate immune system, inflammatory arthritis, mouse model and therapeutic targeting

Session Information

Date: Sunday, November 13, 2016

Title: Rheumatoid Arthritis – Animal Models - Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: The transmembrane protein VISTA, is a member of the B7/CD28 family of immune modulator proteins and can function as a negative immune checkpoint regulator through a currently undefined molecular mechanism(s). VISTA is expressed on myeloid cells and activated T-lymphocytes. Interestingly, qPCR analyses showed VISTA mRNA (human ortholog C10orf54) is expressed abundantly in human rheumatoid synovial tissue. The importance of VISTA expression on myeloid cells was investigated in the collagen-II antibody induced arthritis (CAIA) model.

Methods: Joint targeted inflammation was initiated in the CAIA model by passive-immunization of mice with anti-type-II collagen monoclonal antibodies (5-Clone Cocktail, Chondrex, Seattle) and intraperitoneal injection of LPS, 3 days afterwards. The CAIA model does not require lymphocytes for induction of transient, immune-complex driven joint inflammation (duration 14-15 days), but does require complement activation, neutrophils and monocytes. The arthritic response was evaluated for (1) DBA/1J mice treated with anti-VISTA antibody MH5A (Biolegend) versus hamster IgG as control, and also for (2) VISTA-deficient mice versus wild type, C57/B6 mice.

Results: A sustained attenuation of paw swelling compared to controls was observed from approximately 6-13 days after initiation, for mice treated with anti-VISTA monoclonal antibody MH5A, and for VISTA-deficient mice. Histologic analysis of all major joints involved (knees, ankles, paws) indicated overall reduced joint inflammation/damage in VISTA deficient mice compared to controls. Since C5a generation is crucial to CAIA development, levels of C5a in plasma of wild type and VISTA-deficient mice were determined by ELISA 5 days after passive immunization and found to be equivalent. However, FACS analyses of phagocytic cells isolated from bone marrow as well as in peripheral blood of both arthritic and non-arthritic VISTA-deficient mice consistently displayed reduced C5a receptor expression on neutrophils and on bone marrow derived macrophages. Consistent with these findings, acute C5a receptor responses (ERK, AKT phosphorylation) and chemotaxis to C5a were also diminished in macrophages cultured from VISTA deficient mice.

Conclusion: These findings implicate VISTA in arthritic pathology for the first time, possibly due to a role in recruitment of phagocytes to joints. Antibodies reactive with VISTA may be useful therapeutic agents for autoimmune arthritis where immune-complexes drive joint damage.

Disclosure: R. Fava, None; S. Ceeraz, None; S. Eszterhas, None; P. Sergent, None; C. Burns, None; M. Vincenti, None.

To cite this abstract in AMA style:

Fava R, Ceeraz S, Eszterhas S, Sergent P, Burns C, Vincenti M. Deficiency of Transmembrane Protein VISTA (V-domain Immunoglobulin Suppressor of T-cell Activation) Ameliorates Murine Collagen-II Antibody-Induced Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/deficiency-of-transmembrane-protein-vista-v-domain-immunoglobulin-suppressor-of-t-cell-activation-ameliorates-murine-collagen-ii-antibody-induced-arthritis/. Accessed .

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