The immunological and vascular effects of IL-6 signalling in transplant arteriosclerosis

Author: 
Date created: 
2019-07-08
Identifier: 
etd20405
Keywords: 
Heart transplantation
Alloimmune response
Vascular injury
IL-6
Cell mediated immunity
Humoral response
Abstract: 

Transplant arteriosclerosis (TA) is a pathological vascular condition that is a main cause of chronic rejection and eventual failure of cardiac transplants. TA is caused by the activation of T cells towards allogeneic antigens expressed by vascular cells, which results in T cell-mediated injury and dysfunction of allograft arteries. T cells also support the activation and secretion of donor specific antibodies (DSAs) by B cells that contribute to the pathogenesis of TA. Interleukin-6 (IL-6) is secreted within hours of surgical transplantation and plays an important role in activation of allogeneic immune responses and regulation of vascular processes that influences TA. There are two main mechanisms by which IL-6 can signal to cells, classic and trans, that are distinguished by whether it binds to membrane bound or soluble forms of its receptor (IL-6R). In classic signalling IL-6 binds to IL-6R on the surface of cells. In trans-signaling IL-6 binds to soluble IL-6R. In both scenarios, the IL-6/IL-6R complex associates with the signalling subunit gp130 on cell membranes to transduce intracellular signalling events. Interestingly, IL-6 classic and trans-signalling have distinct biological outcomes. I examined the mechanism by which IL-6 classic and trans signalling contributes to immune activation in TA and characterized the biological outcomes of IL-6 signalling in endothelial cells. IL-6 classic and trans signalling were redundant for the activation of peripheral T cells that cause TA. However, eliminating IL-6R expression in T cells significantly reduced the development of DSAs in the serum of graft recipients, suggesting that IL-6 classic signalling in T cells may be required for antibody-mediated pathology in TA. In addition to activating immune cells, IL-6 acts on endothelial cells to induce inflammation and protect the vasculature from injury. IL-6 trans signalling in ECs significantly induced STAT-3, ERK1/2 and Akt activation. This signalling mechanism was needed for ICAM upregulation and the secretion of inflammatory cytokines by IL-6, indicating that IL-6 trans-signaling drives inflammatory activation of ECs. IL-6 classic signalling induced ERK1/2 and Akt activation but not STAT3 and was sufficient to stimulate the secretion of IL-8 and to protect ECs from cell death caused by serum deprivation but did not induce other inflammatory processes in ECs. My results suggest that IL-6 trans and classic signalling differentially affect inflammatory and survival responses in endothelial cells, which may have implications for understanding the vascular effects of IL-6R blockade in patients. Overall, my findings provide new insight into the immune and vascular effects of IL-6 in transplantation.

Document type: 
Thesis
Rights: 
This thesis may be printed or downloaded for non-commercial research and scholarly purposes. Copyright remains with the author.
File(s): 
Senior supervisor: 
Jonathan Choy
Department: 
Science: Department of Molecular Biology and Biochemistry
Thesis type: 
(Thesis) M.Sc.
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