PREVENTION OF ACUTE MURINE CARDIAC ALLOGRAFT-REJECTION - ANTI-CD4 OR ANTIVASCULAR CELL-ADHESION MOLECULE ONE MONOCLONAL-ANTIBODIES BLOCK ACUTE REJECTION BUT PERMIT PERSISTENT GRAFT-REACTIVE ALLOIMMUNITY AND CHRONIC TISSUE REMODELING

We treated C57BL/6 mouse recipients of DBA/2 cardiac allografts with a nti-CD4 monoclonal antibodies (mAb) or anti-vascular cell adhesion mol ecule 1 mAb to promote long-term allograft survival and subjected both the recipient animals and the long-surviving allografts to a battery of histologic and immunologic tests. The results were similar regardle ss of the mAb used for antirejection therapy. At all tested times afte r transplantation, the allografts displayed histologic evidence of ong oing microvascular endothelial activation and interstitial leukocytic infiltration. Reverse transcription polymerase chain reaction analyses revealed continuous intragraft expression of messenger RNA for interl eukin 1, interleukin 2, interleukin 4, interleukin 6, tumor necrosis f actor, interferon gamma, and transforming growth factor beta. Al graft s had histologic evidence of ongoing vascular and parenchymal tissue r emodeling, including interstitial fibrosis and vascular neointimal hyp erplasia. The graft recipients retained limiting dilution analysis-det ectable, donor-reactive cytolytic T lymphocyte, and helper T lymphocyt e in their spleens and produced high liters of donor-reactive alloanti bodies. Variable amounts of allogeneic microchimerism were: detectable in some, but not all of the long-surviving graft recipients. In gener al, these observations indicate that (1) a similar immune status is ac hieved in long-surviving allografts and their recipients when either a nti-CD4 mAb or antivascular cell adhesion molecule-1 mAb was used for antirejection therapy, in spite of the. major differences in lineage a nd distribution of cells targeted by these two mabs, (2) this immune s tatus is characterized by continuous, long-term inflammatory and immun e processes very similar to those observed during acute allograft reje ction, and (3) in spite of these processes the allografts continue to function, although they invariably develop a chronic rejection-like hi stopathologic condition that may ultimately limit g-raft function In t his regard, the recipients of long-surviving allografts do not seem to be tolerant of their graft alloantigens.