Interplay Between Innate And Adaptive Immunity In Kidney Allograft Rejection
Funder
National Health and Medical Research Council
Funding Amount
$403,101.00
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 ....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.Read moreRead less
How The Kidney Is Injured By CD8+ Cells In Vasculitis
Funder
National Health and Medical Research Council
Funding Amount
$928,780.00
Summary
People with severe kidney disease often have inflammation in the small blood vessels within their kidneys, known as vasculitis. Human observational studies suggest that a type of immune cell, the CD8+ cell, may be critical to disease outcome, but there is no functional evidence for this. The current studies will define the role of these CD8+ cells in disease so that better treatments for humans with vasculitis can be considered.
Mechanisms Of T Cell Mediated Injury In Renal Vasculitis
Funder
National Health and Medical Research Council
Funding Amount
$133,351.00
Summary
Anti-MPO glomerulonephritis (GN) is an aggressive disease causing severe and permanent injury to kidneys. This disease is thought to be due to an immune-mediated response to a protein (MPO) in neutrophils (a type of white blood cell). There is some evidence that other immune cells, CD4+ T cells, may be important in this disease. Experiments using models of anti-MPO GN will aim to define the role and mechanisms by which CD4+ T cells cause inflammation in the kidney.
The Role Of Regulatory T Cells In Rapidly Progressive Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$581,113.00
Summary
Inflammation of the kidneys is an important, yet poorly understood cause of kidney disease in Australia. As part of our endogenous defenses against inflammation, we have cells called regulatory T cells that dampen inflammation and are protective. This project will define the role of some of these cells and examine potential ways to use them do dampen kidney inflammation.
Defining The Role Of Kidney CD103+Dendritic Cells For Treatment Of Chronic Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$599,431.00
Summary
Chronic kidney disease (CKD) is a major cause of death and morbidity. Current treatments for CKD are not effective and new therapeutic approaches are needed. Dendritic cells (DCs) are key immune cells and play a central role in kidney disease. We recently found that a major DC subset called CD103+ DCs harmed the kidney in an animal model of human CKD. This study is to determine how CD103+ DCs cause kidney damage, and how to target CD103+ DCs for development of new therapies for human CKD.
Antigen-specific Regulatory T Cells And HLA Associations In Autoimmune Renal Disease
Funder
National Health and Medical Research Council
Funding Amount
$128,224.00
Summary
Glomerulonephritis (GN), a common cause of kidney failure, usually results from an immune system attack on the kidneys. Current treatments suppress the whole immune system, making patients vulnerable to infection. We aim to harness the body’s protective immune cells (Tregs) as a potential GN treatment. Using mice genetically programmed to mimic a human GN, we will test if specifically targeted Tregs protect mice from disease. We will also test how they affect blood samples from humans with GN.
Targeting Tregs Using Chimeric Antigen Receptors (CARs) For The Treatment Of Autoimmune Renal Disease
Funder
National Health and Medical Research Council
Funding Amount
$845,519.00
Summary
Chronic Kidney Disease is one of the major causes of death in Australia. Therapeutic success with regulatory T cells (Tregs) capable of targeting autoimmune kidney disease would have major clinical implications. In the proposed study, we will use Chimeric Antigen Receptors (CARs) T cells by redirecting them to diseased organs, protect against kidney injury. These CAR T cells will recognise renal antigens and target immune cells and antibodies to limit kidney damage.