Indirect alloreactivity and chronic rejection

Background. The relative contribution of the direct versus indirect pathway of T-lymphocyte alloreactivity to the development of chronic rejection is incompletely understood. Utilizing a murine model of cardiac allograft vasculopathy (CAV) and a recipient strain with markedly reduced capacity for indirect alloreactivity, we sought to define the importance of indirect allorecognition in CAV. Methods. The cells from H2-M mutant mice are unable to present intact protein antigens via class II molecules and have a markedly reduced capacity to present exogenous peptides. B6C.H-2(bm12) strain donor hearts were transplanted into either C57Bl/6 wild-type (WT) or H2-M mutant mice (on C57Bl/6 background). Recipients were killed on day 24. T lymphocyte and macrophage infiltration were graded immunohistochemically. Intimal lesions were measured morphometrically. Results. Donor hearts in WT recipients developed significant intimal lesions, as expected (50 7%). Moreover, the donor hearts in H2-M mutant mice also developed comparable intimal lesions (52 +/- 9%, P=NS vs. WT). Furthermore, the extent of T lymphocyte and macrophage infiltration was similar in both groups. Conclusions. This study demonstrates that a markedly reduced capacity for indirect alloreactivity does not affect the severity of intimal lesions in this model of CAV. The findings of this study question the role of indirect alloreactivity as the sole pathway of allorecognition leading to chronic rejection.