Regulated interleukin-10 expression prevents chronic rejection of transplanted hearts.
OBJECTIVE
Interleukin-10 is a pleiotrophic cytokine with variable effects on the alloimmune response, depending on the experimental model system. The purpose of this study was to determine the role of regulated interleukin-10 expression on the development of chronic rejection in heart transplantation, or cardiac allograft vasculopathy.


METHODS
Donor hearts from B6.C-H2(bm12) mice were transplanted into wild-type and interleukin-10 transgenic recipients. In interleukin-10 transgenic recipients, murine interleukin-10 cytokine is produced under the control of human interleukin-2 promoter. Donor hearts were sacrificed at days 7 and 24. No immunosuppression was used. Intimal proliferation was measured morphometrically. Intragraft cellular infiltrate was defined by both immunohistochemistry and flow cytometry. Intracellular cytokine staining assay was performed to determine both the type and source of intragraft cytokines.


RESULTS
Hearts transplanted into wild-type recipients developed severe cardiac allograft vasculopathy by 24 days. Intimal lesions were absent in the donor hearts transplanted into interleukin-10 transgenic recipients. The number of graft-infiltrating T lymphocytes and the percentage of interleukin-2/interferon-gamma producing T lymphocytes were markedly reduced in interleukin-10 transgenic recipients. Finally, the overexpression of interleukin-10 resulted in the decline of graft-infiltrating macrophages at all time points.


CONCLUSIONS
Regulated expression of interleukin-10 inhibits cardiac allograft vasculopathy development via reduction of mononuclear cell recruitment and alteration of their cytokine profile. This strategy may prove beneficial in controlling the alloimmune response in solid organ transplants.
Fischbein
Michael P
MP
Department of Surgery, University of California, Los Angeles, USA.
Yun
James
J
Laks
Hillel
H
Irie
Yoshihito
Y
Oslund-Pinderski
Laura
L
Fishbein
Michael C
MC
Bonavida
Benjamin
B
Ardehali
Abbas
A
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006084:Graft Rejection / Q000378:metabolism* / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000096:biosynthesis*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008955:Models, Cardiovascular; D009000:Monocytes / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology; D015203:Reproducibility of Results; D013223:Statistics as Topic; D013601:T-Lymphocytes / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers; D015815:Cell Adhesion Molecules; D016207:Cytokines; D016753:Interleukin-10