HOST-GRAFT INTERACTIONS OF CNS CHROMAFFIN CELL IMPLANTS

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DESCRIPTION (Applicant's Abstract): We have shown that pain sensitivity can be reduced by transplanting adrenal medullary tissue or isolated chromaffin cells into such CNS pain modulatory regions in the rat at the midbrain periaqueductal gray (PAG) or extra- parenchymally in the subarachnoid space of the dorsal lumbar spinal cord. We have obtained promising results in preliminary clinical studies using allografts of adrenal medulla to relieve cancer pain. In addition to allografts, we have found that bovine chromaffin cells survive well in the rat CNS. Xenografts are a potentially important untapped donor source that may overcome the limited availability of human donors. However, before large scale clinical implementation of these procedures is undertaken, it is important to obtain in-depth information on host response to chromaffin cell grafts in laboratory animals. It is critical to establish the consequences of introducing foreign tissues, both allo- and xenogeneic, into the host CNS. These studies will focus on a determination of host CNS responses to adrenal medullary tissue and isolated chromaffin cell transplants using techniques recently developed in our laboratory. In addition, the stability of the transplants and host-graft integration, and conditions necessary for continue graft maintenance, are critical and will be addressed. Specifically, the proposed studies will analyze immunological responses to allografts and xenografts, implanted both intra- and extraparenchymally. These will include staining for induction of major histocompatibility antigens (MHC I and II). We will also determine donor-recipient histocompatibility with the mixed lymphocyte reaction (MLR). The necessity for continual or short-term immunosuppression and the effects of addition of putative antigen-presenting cells will also be assessed. Graft survival and host responses will be evaluated following immunologic challenges, such as transient disruption of the blood-brain barrier and systemic sensitization. Transplant-induced changes in blood-brain barrier permeability and uptake properties, glial reactivity and cellular infiltration will be studied. Our previous findings have revealed that both transplanted isolated chromaffin cells and adrenal medullary tissue become well integrated and participate in forming synapses with host neuronal processes. The effect of trophic factors on cultured cells and transplanted cells will be compared. A strength of these proposed studies is the ability to correlate graft survival and integration with antinociceptive activity.