Chronic blockade of CD28-B7-mediated T-cell costimulation by CTLA4Ig reduces intimal thickening in MHC class I and II incompatible mouse heart allografts.
BACKGROUND
Chronic rejection develops in MHC class I/II-mismatched mouse allografts with arteriosclerosis and intragraft T-cell activation. Blockade with murine CTLA4Ig was used to study the role of CD28-B7 T-cell costimulation in this model of vascular thickening.


METHODS
CBA/CaJ to C57BL/6J vascularized cardiac transplants were treated with murine CTLA4Ig delivered as a single dose (250 microg i.p.) on day 2 or chronically (100 microg i.p. on days 0, 2, and 4 and biweekly). Graft survival, function, and quantitative vessel analysis were compared with those of a reference group treated with anti-CD4 (days 1-4).


RESULTS
Day 2 and chronic murine CTLA4Ig treatment prolonged graft survival (mean times and percentage of grafts surviving >75 days) and preserved graft function (measured by palpation scores). However, histology showed that chronic murine CTLA4Ig grafts had little parenchymal infiltration and less prominent vascular occlusion than day 2 murine CTLA4Ig-treated or 4-day anti-CD4-treated grafts. Quantitative analysis showed that the percentage of diseased vessels and the percentage of luminal occlusion were high in the day 2 murine CTLA4Ig group (78+/-20% and 41+/-12%, respectively, n=5) and the anti-CD4 group (94+/-9% and 52+/-17%, respectively, n=9, P=NS). In contrast, the frequency and severity of vessel thickening were significantly reduced in the chronic murine CTLA4Ig group (57+/-13% and 24+/-13%, respectively, n=10, P<0.03).


CONCLUSIONS
In this model with MHC class I and II disparities, day 2 murine CTLA4Ig treatment improved survival and function but did not ameliorate vascular thickening. However, ongoing blockade of CD28-B7 costimulation conferred protection against vascular thickening.
Glysing-Jensen
T
T
Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Räisänen-Sokolowski
A
A
Sayegh
M H
MH
Russell
M E
ME
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000276:immunology / Q000517:prevention & control; D018122:B7-1 Antigen / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D006085:Graft Survival; D006321:Heart / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology* / Q000379:methods / Q000473:pathology; D006648:Histocompatibility; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007111:Immunity, Cellular; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D017539:Tunica Intima / Q000473:pathology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept