Receptors for C3a and C5a modify dendritic cell function in alloreactive T cell responses and allograft rejection

Lead Research Organisation: King's College London
Department Name: Immunology Infection and Inflam Diseases

Abstract

Defence against invasive organisms such as bacteria and viruses begins with an immediate inflammatory response, which is followed a few days later by more lasting immunity provided by white cells known as T lymphocytes. In much the same way that T lymphocytes, with the help of the innate inflammatory response, eliminates invading organisms, these defences recognise as foreign, organ transplants from an unrelated donor, leading to rejection of the donor organ. By studying proteins of the inflammatory response called complement, work in our laboratory and at other centres has already shown that T lymphocytes can only function properly in the presence of complement; without complement transplanted kidney survives for much longer. Our aim is to learn how complement drives the immune response and to develop treatments that prevent complement from causing disease. We believe that complement acts on the immune system through an intermediary type of cell (dendritic cell) that passes on instructions to resting T lymphocytes alerting them to the presence of foreign material. We will carefully examine the ability of dendritic cells to detect activated complement fragments and examine whether blockade of this ability of dendritic cells to sense complement activation will blunt the capacity of the immune system to generate harmful T cells, and thus reduce the risk of transplant rejection. If we are successful in showing how complement stimulates harmful T cells, this may offer a valuable means to block the immune response against organ transplants and thus prevent rejection.

Technical Summary

Accumulating evidence suggests that local production of complement (C) in antigen presenting cells (APCs), such as dendritic cells (DCs), is crucial for full T cell activation and development of a Th1 phenotype; however, the underlying mechanisms of action of complement on APCs are uncertain. In the proposed research we will test the hypothesis that local production of complement and its activation, at the sites of interstitial space and interface with environment where DCs reside, generate potent inflammatory molecules (e.g. C3a, C5a) that bind to their receptors on DCs resulting in DC activation; and this process is critical for the development of DC function and DC-mediated T cell responses. To investigate this, we will initially assess if C3a and C5a liberated in these circumstances bind to their respective receptors on myeloid DCs and lead to DC activation. We will then determine if such C3a receptor (C3aR) or C5a receptor (C5aR) engagement modulates DC effector functions in alloreactive T cell response in vivo and in vitro, using C3aR-/- or C5aR-/- DCs, C3a or C5a agonists/antagonists. Once we have established if blockade or deficiency of C3aR (or C5aR) in DCs reduces the potency of DCs to stimulate alloreactive T cells and promotes regulatory T cell development, we will study the relevance of the findings to solid-organ transplantation. Using a model of mouse kidney transplantation that is well established in our laboratory, we will investigate if donor kidney and/or recipients lacking C3aR (or C5aR) exhibit improved allograft outcomes. In support of this hypothesis, our preliminary data show that C3aR and C5aR are synthesised in myeloid DCs, and that C3a is present in DC culture supernatant. Additionally, we find that blockade or deficiency of C3aR (or C5aR) in DCs leads to a tolerogenic DC cytokine profile with lowered capacity by about two-thirds for alloreactive T cell stimulation. Thus, C3aR (and/or C5aR) engagement on APCs offers a potential mechanism by which local production of complement regulates the antidonor T cell response, and could therefore contribute to allograft rejection. We anticipate the proposed research will inform our understanding of the way in which innate immunity regulates the adaptive immune response via complement receptor. Manipulation of C by receptor blockade could provide a new direction for preventing immune mediated injury including transplant rejection.

Publications

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Asgari E (2010) Complement in organ transplantation. in Current opinion in organ transplantation

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Bartel G (2013) Donor specific transplant tolerance is dependent on complement receptors. in Transplant international : official journal of the European Society for Organ Transplantation

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Lalli PN (2009) Locally produced and activated complement as a mediator of alloreactive T cells. in Frontiers in bioscience (Scholar edition)

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Li K (2013) Anaphylatoxins in organ transplantation. in Seminars in immunology

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Li Q (2010) Deficiency of C5aR prolongs renal allograft survival. in Journal of the American Society of Nephrology : JASN

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Peng Q (2012) C3a and C5a promote renal ischemia-reperfusion injury. in Journal of the American Society of Nephrology : JASN

 
Title Membrane targetted C5a receptor inhibitor 
Description Inhibitor of inflammation 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Work in progress