PMID- 25286051 OWN - NLM STAT- MEDLINE DCOM- 20150727 LR - 20150512 IS - 1534-6080 (Electronic) IS - 0041-1337 (Linking) VI - 98 IP - 12 DP - 2014 Dec 27 TI - Anti-interleukin 6 receptor antibodies attenuate antibody recall responses in a mouse model of allosensitization. PG - 1262-70 LID - 10.1097/TP.0000000000000437 [doi] AB - BACKGROUND: Interleukin (IL)-6 is a regulatory cytokine for T helper type 17 (Th17) and Treg cells and a potent stimulus for B/plasma cells. The current study evaluated the effect of IL-6 receptor (IL-6R) blockade with an antiYIL-6R monoclonal (mMR16-1) in alloantibody recall responses. METHODS: A mouse model of human leukocyte antigen (HLA).A2 sensitization was used for studies to evaluate the efficacy of antiYIL-6R on alloantibody recall responses and to examine the impact of IL-6R blockade on Th17, Treg, follicular T helper (Tfh) and plasma cells using multiparameter flow cytometry, flow antibody binding, and enzyme-linked immunospot (ELISpot) assay. RESULTS: Re-exposure of C57BL/6 mice to HLA.A2(+) skin allografts resulted in a surge of donor-specific (antiYHLA.A2) immunoglobulin (Ig)G antibodies. AntiYIL-6R treatment significantly decreased but did not eliminate alloantibody responses (IgG mean fluorescence intensity, 486 T 153 vs. control 792 T 193, P = 0.0076). Flow cytometry analysis showed that antiYIL-6R treatment resulted in reduction of IL-21+CD4+ (Th17) cells (P = 0.006 vs. control) and CXCR5(+)CD4(+) Tfh cells (P = 0.04), but increased foxp3(+)CD4(+) (Treg) cells in the CD4(+) population (P =0.04 vs. control). The IgG ELISpot experiments showed a significant reduction of IgG spots in the bone marrow and the spleen cells from the antiYIL-6RYtreated mice. In vitro treatment of mouse hybridoma (PA2.1) cultures with antiYIL-6R decreased IgG spot formation but had limited effect on cell proliferation. CONCLUSION: The data indicate that antiYIL-6R therapy attenuates alloantibody recall responses by modulating a number of immune regulatory and effector cells, including Th17, Tfh, Treg, and importantly, the long-lived plasma cells in the bone marrow. FAU - Kim, Irene AU - Kim I AD - 1 Comprehensive Transplant Center at Cedars-Sinai Medical Center, Los Angeles, CA 2 Address correspondence to: Gordon Wu, M.D., Comprehensive Transplant Center, Cedars-Sinai Medical Center, 8900 Beverly Blvd. Los Angeles, CA 90048. FAU - Wu, Gordon AU - Wu G FAU - Chai, Ning-ning AU - Chai NN FAU - Klein, Andrew S AU - Klein AS FAU - Jordan, Stanley AU - Jordan S LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Transplantation JT - Transplantation JID - 0132144 RN - 0 (Antibodies, Monoclonal) RN - 0 (CXCR5 protein, human) RN - 0 (FOXP3 protein, human) RN - 0 (Forkhead Transcription Factors) RN - 0 (Foxp3 protein, mouse) RN - 0 (HLA-A2 Antigen) RN - 0 (Immunoglobulin G) RN - 0 (Interleukin-17) RN - 0 (Isoantibodies) RN - 0 (Receptors, CXCR5) RN - 0 (Receptors, Interleukin-6) SB - IM MH - Animals MH - Antibodies, Monoclonal/immunology MH - Bone Marrow Cells/cytology MH - CD4-Positive T-Lymphocytes/cytology MH - Cell Differentiation MH - Cell Proliferation MH - Disease Models, Animal MH - Enzyme-Linked Immunosorbent Assay MH - Flow Cytometry MH - Forkhead Transcription Factors/*metabolism MH - HLA-A2 Antigen/immunology MH - Humans MH - Immunoglobulin G/immunology MH - Interleukin-17/immunology MH - Isoantibodies/*immunology MH - Lymphocytes/cytology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Receptors, CXCR5/metabolism MH - Receptors, Interleukin-6/antagonists & inhibitors/*immunology MH - Spleen/cytology MH - Transplantation, Homologous EDAT- 2014/10/07 06:00 MHDA- 2015/07/28 06:00 CRDT- 2014/10/07 06:00 PHST- 2014/10/07 06:00 [entrez] PHST- 2014/10/07 06:00 [pubmed] PHST- 2015/07/28 06:00 [medline] AID - 10.1097/TP.0000000000000437 [doi] PST - ppublish SO - Transplantation. 2014 Dec 27;98(12):1262-70. doi: 10.1097/TP.0000000000000437.