Background: Chronic Rejection remains the leading cause of late death among heart transplant recipients. CD8 lymphocytes have emerged as critical participants in the development of chronic rejection. However, the effector mechanism(s) of CD8 lymphocyte-mediated chronic rejection is not known.
Methods: To study CD8 lymphocyte effector functions independently of CD4 lymphocytes, we adaptively transferred wild type CD8 lymphocytes (Group I, n=4), Fas Ligand (FasL) knockout CD8 lymphocytes (Group II, n=4), Perforin knockout CD8 lymphocytes (Group III, n=4), and IFN-γ knockout CD8 lymphocytes (Group IV, n=4) to nude mice. These mice underwent heterotopic heart transplantation. Donor hearts were harvested on day 40 post transplantation and analyzed for cellular infiltrate and intimal thickening.
Results: In Group I, donor hearts were infiltrated with activated wild type CD8 lymphocytes and displayed significant intimal lesions (31+8%). In Groups II and III, FasL -/- and Perforin -/- CD8 lymphocytes also infiltrated the donor hearts and lead to similar severity of intimal lesions (FasL-/- 30+7%, Perforin -/- 32+6%). However, in Group IV, IFN-γ -/- CD8 lymphocytes were found in the donor hearts, but importantly minimal intimal lesions were present ( 4+2%, p<0.05 when compared to groups I-III).
Conclusion: These findings suggest that 1) cytotoxic pathways such as FasL and perforin are not necessary for CD8 lymphocyte mediated chronic rejection, and 2) production of IFN-γ by CD8 lymphocytes is the critical step in the development of chronic rejection. Newer immunosuppressive therapies designed to counter chronic rejection need to target IFN-γ production by CD8 lymphocytes.

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