Role of CD8+ lymphocytes in chronic rejection of transplanted hearts.
BACKGROUND
The contribution of CD8(+) lymphocytes to the pathogenesis of cardiac allograft vasculopathy, or chronic rejection in heart transplants, remains undefined. We used both major histocompatibility complex class I mismatched and major histocompatibility complex class II mismatched models of cardiac allograft vasculopathy to characterize the role of CD8(+) lymphocytes in the development of cardiac allograft vasculopathy.


METHODS
Donor hearts from B10.A mice were transplanted into B10.BR recipients (major histocompatibility complex class I mismatched). Donor hearts were harvested at 1, 7, 14, and 30 days after transplantation and (1) quantitated morphometrically for lesion development, (2) stained immunohistochemically, or (3) digested for isolation of graft-infiltrating cells. The cytotoxic phenotype of graft-infiltrating CD8(+) lymphocytes was determined with flow cytometry. Intracellular cytokine staining of CD8(+) and CD4(+) lymphocytes for interleukin 2, interferon g, interleukin 4, and interleukin 10 was performed with 2-color flow cytometry. Finally, B6.C-H2(bm12) donor hearts were transplanted into either C57BL/6 wild-type (major histocompatibility complex class II mismatched) or CD8 -/- knockout recipients and examined for the development of cardiac allograft vasculopathy.


RESULTS
In the major histocompatibility complex class I mismatched model, CD8(+) lymphocytes were the predominant T-lymphocyte subset that infiltrated the allografts and demonstrated markers of activation. The intracellular cytokine-staining assay demonstrated that CD8(+) lymphocytes were the primary sources of allograft interleukin 2 and interferon gamma. Intimal lesions developed in the allografts by day 14 (12.0% +/- 4.0%) and further increased by day 30 (44.0% +/- 5.0%). In the major histocompatibility complex class II mismatched model, the donor hearts in the CD8 -/- knockout recipients had substantially less severe intimal lesions when compared with the donor hearts in wild-type recipients (19.0% +/- 6.0% vs 50.0% +/- 7.0%, respectively; P <.05).


CONCLUSIONS
In both major histocompatibility complex class I and II mismatched models, CD8(+) lymphocytes contribute significantly to chronic rejection. The findings of this study suggest that control of chronic rejection requires interventions directed at CD8(+) lymphocytes.
Fischbein
Michael P
MP
Division of Cardiothoracic Surgery, Department of Surgery, University of California, Los Angeles, UCLA Medical Center, Los Angeles, CA 90095, USA.
Yun
James
J
Laks
Hillel
H
Irie
Yoshihito
Y
Fishbein
Michael C
MC
Bonavida
Benjamin
B
Ardehali
Abbas
A
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002908:Chronic Disease; D003331:Coronary Vessels / Q000276:immunology / Q000503:physiopathology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000503:physiopathology*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000276:immunology / Q000503:physiopathology; D013997:Time Factors