Hannah Valantine-von Kaeppler

My lab is focused on understanding the mechanism mediating acute and chronic allograft failure, in particular on the role of microvascular injury in acute allograft failure and the mechanisms of mediating transplant coronary artery disease.

1. Role of microvascular injury in acute allograft failure. We observed decreased cardiac allograft function in patients to be significantly associated with loss of microvascular cell surface markers, consistent with altered biology of the vascular endothelium or injury, and with up-regulation of cytokines such as IL-6, IL-10, TGF-b, and TNF-a. Decreased cardiac allograft function, in particular diastolic dysfunction, was highly predictive of allograft vascular disease and poor outcome in long-term patients. To further characterize cellular and molecular mechanisms we developed quantitative methods to monitor allograft function and correlate it with cytokine expression in a rat heterotopic transplant model. We developed echocardiographic markers of systolic and diastolic function and found decreasing systolic and diastolic function highly correlated with up-regulation of IL-6 expression. Correlation with other key cytokines is now being examined. Future studies will determine if up-regulation of cytokine expression occurs in vascular endothelial cells or endogenous cells of the graft vs. infiltrating mononuclear cells. We will then inhibit transcription genes and block translation with cytokine monoclonal antibodies.

2. Mechanisms mediating allograft dysfunction. We observed the major risk factors for transplant atherosclerosis in patients to be metabolic (hyperglycemia, hypertriglyceridemia, and low HDL). To further study cellular and molecular mechanisms mediating this process, we recapitulated metabolic abnormalities in the rat heart transplant model and confirmed rapid development of transplant atherosclerosis. Later we will characterize the cytokines involved in metabolically deranged animals which develop rapid atherosclerosis, and examine the relative contributions of hyperlipidemia, hyperglycemia, and alloimmunity in this new model of transplant atherosclerosis.