Interplay between innate and adaptive immunity in kidney allograft rejection

Funded Activity Summary

Acute allograft rejection (AR) still occurs in up to 40% of patients and is the major cause of graft loss during the first year after kidney transplantation. Even when treated, AR causes graft damage and is a major risk factor for premature graft loss due to chronic allograft nephropathy. Graft loss due to rejection returns the patient to dialysis and thus incurs medical costs in excess of $50,000 p.a. and reduces the duration and quality of life of the patient. Thus, AR directly and indirectly places a major burden upon patients, transplant services and the Australian community. AR occurs because of an adaptive alloimmune response mediated by T cells. The allografts also elicit an innate response and recent work has demonstrated both the prominence of the innate response and its essential role in facilitating adaptive alloimmunity. T cells are a component of the adaptive response and are prominent within rejecting allografts. NKG2D and toll like receptors (TLRs) are components of innate immune system. Our data demonstrates that ischemia reperfusion injury (IRI) causes upregulation of NKG2D ligand RAE-1 by kidney cells and TLR4 expression in kidney IRI and AR and that NKG2D expression is upregulated during kidney AR, and is expressed by intragraft CD8+ cells. Our results indicate that an interaction between innate and adaptive immunity may promote AR. We aim to determine whether: 1) TLR4 is required for the development of IRI to kidney and RAE-1 expression. 2) blockade of the interaction between NKG2D and its ligand RAE-1 expressed on the graft can attenuate AR and consequently prolong graft survival. 3) combined blockade of innate plus adaptive co-stimulatory molecules is more effective than either alone. This work will dissect the key interactions between innate and adaptive immunity in the allograft response and identify new targets for the prevention and treatment of allograft rejection.

Funded Activity Details

Start Date: 01-01-2006

End Date: 01-01-2008

Funding Scheme: NHMRC Project Grants

Funding Amount: $403,101.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Nephrology and Urology

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

Acute kidney allograft rejection | Innate and adaptive immunty | Kidney Transplantation | Kidney transplantation | Nephrology | Renal allograft rejection | Renal failure | T lymphocytes

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