Role of the CTLA4 pathway in hyporesponsiveness induced by intratracheal delivery of alloantigen.
BACKGROUND
The authors previously reported that intratracheal delivery (ITD) of donor alloantigen induced donor-specific hyporesponsiveness to C57BL/10 cardiac allografts in CBA recipients and that blockade of the B7 pathways abrogated that hyporesponsiveness. In this study, the authors used a CD28-deficient model to evaluate which signal, either through CD28 or cytotoxic T-lymphocyte-associated antigen (CTLA4), is involved in the induction of hyporesponsiveness.


METHODS
Seven days before transplantation of hearts from C3H/HeJ (H2k) mice into C57BL/6 (H2b) or CD28-deficient (C57BL/6 background) mice, the transplant recipients were given ITD of donor splenocytes (1 x 10(7)), alone or in combination with human CTLA4-immunoglobulin (Ig) (200 microg).


RESULTS
ITD of C3H splenocytes induced donor-specific hyporesponsiveness to C3H cardiac grafts in C57BL/6 recipients (graft median survival time [MST], 40 days). Administration of CTLA4-Ig concurrently with ITD abrogated the prolonged allograft survival (MST, 12 days). Interestingly, ITD of C3H splenocytes induced prolonged survival of C3H allografts in CD28-deficient recipients (MST, 55 days). Furthermore, administration of CTLA4-Ig combined with ITD of C3H splenocytes abrogated the prolonged survival of C3H allografts in CD28-deficient recipients (MST, 7 days), whereas recipients given isotype-control antibody in combination with ITD of splenocytes had prolonged survival of C3H allografts (MST, 58 days).


CONCLUSIONS
Taken together, the authors' findings indicate that a signal through CTLA4, rather than through CD28, plays an important role in the induction of hyporesponsiveness by ITD of alloantigen in this model.
Shirasugi
Nozomu
N
First Department of Surgery, Teikyo University, Tokyo, Japan.
Akiyama
Yoshinobu
Y
Aramaki
Osamu
O
Shibutani
Sintaro
S
Matsumoto
Kenji
K
Bashuda
Hisashi
H
Yagita
Hideo
H
Okumura
Ko
K
Ikeda
Yoshifumi
Y
Niimi
Masanori
M
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen; D017690:Cell Transplantation; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates / Q000008:administration & dosage; D007519:Isoantigens / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D014019:Tissue Donors; D014132:Trachea / Q000502:physiology*; D023001:Transplantation Tolerance / Q000502:physiology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007519:Isoantigens; D000069594:Abatacept