An agonistic anti-BTLA mAb (3C10) induced generation of IL-10-dependent regulatory CD4+ T cells and prolongation of murine cardiac allograft.
BACKGROUND
The co-inhibitory receptor B and T lymphocyte attenuator (BTLA) has been implicated in the regulation of autoimmunity and may potentially play an important role in allograft tolerance. This study investigated the effect of an agonistic anti-BTLA mAb (3C10) in the fully major histocompatibility complex-mismatched murine cardiac transplantation.


METHODS
CBA mice underwent transplantation of C57BL/6 hearts and received one dose of 3C10 on the day of transplantation (day 0) or four doses of 3C10 on day 0, 3, 6, and 9. Adoptive transfer studies were performed to determine whether regulatory cells were generated. Moreover, to confirm the requirement for regulatory T cell and Th-2 cytokines, anti-interleukin (IL)-2 receptor alpha antibody (PC-61) or anti-IL-10 antibody (JES-2A5) was administered to a 3C10-treated CBA recipient.


RESULTS
CBA mice treated with one and four doses of 3C10 prolonged allograft survival (median survival times [MSTs], 43 and >100 days, respectively). Secondary CBA recipients given whole splenocytes or CD4 cells from primary 3C10-treated CBA recipients had significantly prolonged survival of C57BL/6 hearts (MSTs, >100 in both). Also, flow cytometry studies showed an increased CD4CD25Foxp3 cell population in 3C10-treated mice. Additionally, IL-2 and interferon-γ production were suppressed in 3C10-treated mice, and IL-4 and IL-10 from 3C10-treated CBA mice increased. Moreover, 3C10 directly suppressed alloproliferation in a mixed leukocyte culture. However, administration of PC-61 or JES-2A5 clearly attenuated prolonged survival of 3C10-treated mice (MSTs, 15.5 and 13.5 days, respectively).


CONCLUSIONS
3C10 could control acute rejection by its suppressive effect on alloreactive T cells and induction of IL-10-dependent regulatory CD4 T cells.
1 Department of Cardiovascular Surgery, Teikyo University Hospital, Tokyo, Japan. 2 Department of Immunology, Juntendo University Hospital, Tokyo, Japan. 3 Department of Surgery, Teikyo University, Tokyo, Japan. 4 Department of Cardiovascular and Thoracic Surgery, The 4th Affiliated Hospital of Harbin Medical University, Harbin, China. 5 Address correspondence to: Masanori Niimi, M.D., Ph.D., Department of Surgery, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
Masateru
M
Uchiyama
Xiangyuan
X
Jin
Hironori
H
Matsuda
Hisashi
H
Bashuda
Tomohiro
T
Imazuru
Tomoki
T
Shimokawa
Hideo
H
Yagita
Masanori
M
Niimi
D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D016027:Heart Transplantation / Q000379:methods*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000737:chemistry / Q000378:metabolism*; D007376:Interleukin-2 / Q000276:immunology; D007962:Leukocytes / Q000166:cytology; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011971:Receptors, Immunologic / Q000737:chemistry*; D015375:Receptors, Interleukin-2 / Q000737:chemistry; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*
C587482:3C10 monoclonal antibody, mouse; D000911:Antibodies, Monoclonal; C488868:BTLA protein, mouse; D016207:Cytokines; D007376:Interleukin-2; C584092:PC61 monoclonal antibody; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D016753:Interleukin-10