SUSTAINED ANTI-CD4 CD8 TREATMENT BLOCKS INFLAMMATORY ACTIVATION AND INTIMAL THICKENING IN MOUSE HEART ALLOGRAFTS/

We evaluated inflammatory activation and vascular thickening in a hete rotopic murine heart transplant model. C57BL/6J recipient mice receive d anti-CD4 therapy (days 1 to 4 after transplantation) or sustained, c ombined anti-CD4/CD8 therapy (days 1 to 4, weekly thereafter). Morphom etric analysis of grafts (>95 days) found the mean percentage of vesse l occlusion to be 51.7% in allografts treated with anti-CD4, 8.3% in a llografts treated with sustained anti-CD4/CD8, and 6.7% in isografts. Mean transcript levels of the adhesion molecules P-selectin, intercell ular adhesion molecule 1 (ICAM-1), and leukocyte function-associated a ntigen 1 (LFA-1) and the cytokines interleukin 4 (IL-4), interferon-ga mma (IFN-gamma), inducible nitric oxide synthase (iNOS), allograft inf lammatory factor 1 (AIF-1), and monocyte chemoattractant protein 1 (MC P-1) were measured with reverse transcription-polymerase chain reactio n [RT-PCR] assays using deoxycytidine triphosphate radiolabeled with p hosphorus 32 [P-32-dCTP]. The assays were normalized against grycerald ehyde-3-phosphate dehydrogenase [G3PDH] Levels were found to be signif icantly higher in the anti-CD4 group than in the anti-CD4/CD8 group. A strong correlation was also found between the percentage of luminal o cclusion and the expression of these markers of inflammation (r=.92-.9 9, P<.0001). Sustained therapy involving proximal blockade of CD4 and CD8 interrupts pathways leading to inflammation; and vascular thickeni ng. However, long-term heart allografts in mice treated with a short c ourse of anti-CD4 display an ongoing inflammatory cell activation that culminates in arteriosclerosis. This model may help examine the role of targeted immune factors using knockout mice to identify those causa lly involved in Vessel thickening.