Incidence And Risk Factors For Cancer After Liver And Cardiothoracic Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$301,220.00
Summary
We will examine the incidence of cancer in patients before and after heart, lung, and liver transplantation. We will also examine the risk factors for cancer in these populations, including viral infection, time since transplantation, and the cause of organ failure. We will do this by linking data held by world-class Australian transplantation registries and the national cancer registry. Comparisons with other immune-deficient populations will allow valuable insight into the causes of cancer.
CONTINUING MECHANISTIC STUDIES OF UVA PHOTOIMMUNOPROTECTION
Funder
National Health and Medical Research Council
Funding Amount
$261,113.00
Summary
The UVB portion of sunlight causes sunburn, tanning, skin cancer, and suppresses immune function. Longer wavelength UVA is significantly less damaging, may contribute to photoageing and damage to deeper skin layers, but has been much less well studied. UVB-induced immunosuppression appears to be a prerequisite for skin cancer, and experimental protection from the immunosuppression results also in reduced severity of the long-term skin cancer outcome. We have identified a protective effect by UVA ....The UVB portion of sunlight causes sunburn, tanning, skin cancer, and suppresses immune function. Longer wavelength UVA is significantly less damaging, may contribute to photoageing and damage to deeper skin layers, but has been much less well studied. UVB-induced immunosuppression appears to be a prerequisite for skin cancer, and experimental protection from the immunosuppression results also in reduced severity of the long-term skin cancer outcome. We have identified a protective effect by UVA radiation against UVB-immunosuppression when UVA is administered to mice at non-burning environmentally relevant doses. This was an important and unprecedented finding, and is supported by recent observations also in humans. The aim of the present study is to clarify the mechanisms by which this resistance to UVB-induced immunosuppression is achieved, according to 2 main hypotheses: 1. UVA interferes with the actions of cis-urocanic acid, a natural epidermal UV-photoproduct that appears to initiate the immunosuppression by interacting with histamine. 2. UVA alters the balance of immunological control and thus activates normal antioxidant defences of the skin such as metallothionein and haem oxygenase, which antagonise the apparent oxidative requirement for UVB-immunosuppression. These pathways lead to the prediction that increasing the UVA component of the incident radiation will reduce skin cancer development. Humans typically receive disproportionately large UVA doses sunbathing through a UVB-sunscreen, or in cosmetic sunparlours. The assumption that UVA contributes to UVB skin damage may not be true at moderate UV doses, and a potential for UVA to protect from UVB-suppressed immunity and risk of skin cancer would suggest that broad spectrum sunscreens are contraindicated, and that the UVA effects need to be exploited.Read moreRead less
Patient Tailored Immunity Transplant For The Prevention Of Viral Infections Post Haemopoietic Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$567,967.00
Summary
Blood or bone marrow transplantation can cure leukaemia and related blood disorders, but patients are susceptible to infections in the period early after transplant. Infectious complications remain a leading cause of death among allogeneic transplant recipients. Our research aims to prevent the onset of infection using novel cell therapies to rapidly restore the immune system thus preventing the problems associated with the transplant process.
Multiple Cytomegalovirus Infections: Biological And Evolutionary Significance.
Funder
National Health and Medical Research Council
Funding Amount
$555,776.00
Summary
This project involves the study of cytomegalovirus (CMV) a common viral infection of humans which normally cause little disease. However in individuals whose immune system is suppressed (such as AIDS patients or transplant recipients), or in infection of pregnant women, CMV can cause serious or life-threatening disease in the patient or foetus. An interesting feature of CMV diseases in such patients is that enhanced viral growth and more severe disease is frequently associated with the presence ....This project involves the study of cytomegalovirus (CMV) a common viral infection of humans which normally cause little disease. However in individuals whose immune system is suppressed (such as AIDS patients or transplant recipients), or in infection of pregnant women, CMV can cause serious or life-threatening disease in the patient or foetus. An interesting feature of CMV diseases in such patients is that enhanced viral growth and more severe disease is frequently associated with the presence of multiple strains of CMV in the patient. We suggest that mixed CMV infections provide a survival advantage to the virus, with different strains within the mixed infection assisting the growth of other strains. This would result in increased virus growth overall, and enhanced disease. To study the mechanisms by which multiple infections with different CMV strains may affect both the virus and the host, experiments will be performed using an animal model of CMV, murine cytomegalovirus (MCMV). We will examine the effect of the presence of multiple strains of virus on virus growth and distribution within the infected host. We will also determine if functional MCMV strains are capable of assisting non-functional strains to survive within the host. These studies are relevant to the design of a CMV vaccine, and will be valuable in revealing the ways in which viruses can co-operate within an infection.Read moreRead less
Cancer Incidence In Recipients Of Haematopoietic Stem Cell Transplantation In Australia
Funder
National Health and Medical Research Council
Funding Amount
$408,788.00
Summary
Haematopoietic stem cell transplantation (HSCT) is widely used in Australia to treat patients with haematological cancers. The risk of developing second malignancies after HSCT has been increasingly recognised over recent decades as more and more patients survive. The proposed study will characterise the incidence and risk factors for cancer following HSCT. This information is essential for long-term surveillance and intervention strategies in both specialist and primary care settings.
Pharmacokinetic And Pharmacodynamic Studies Of The Newer Immunosuppressants
Funder
National Health and Medical Research Council
Funding Amount
$406,650.00
Summary
After an organ transplant (such as a liver or kidney transplant), people need to take medicines continually to stop their immune systems from rejecting their new organ. This treatment with immunosuppressant drugs is vital for long-term success of the graft. These drugs are designed to prevent rejection in patients who have received organ transplants (e.g. kidney, liver) and are also being used to treat a variety of autoimmune diseases, including rheumatoid arthritis. However, too many people are ....After an organ transplant (such as a liver or kidney transplant), people need to take medicines continually to stop their immune systems from rejecting their new organ. This treatment with immunosuppressant drugs is vital for long-term success of the graft. These drugs are designed to prevent rejection in patients who have received organ transplants (e.g. kidney, liver) and are also being used to treat a variety of autoimmune diseases, including rheumatoid arthritis. However, too many people are losing transplanted organs, or not achieving remission from their autoimmune diseases, or are experiencing significant illness and sometimes death from over immunosuppression (infection or side effects) because these drugs are not being used in the best way. The quality and duration of life of increasing numbers of Australians is being affected by lack of understanding and application of some basic principles about dosing regimens for these drugs. The aim of this project is to accurately define the best way to dose these newer immunosuppressant drugs in Australian populations, before they become more widely used .Read moreRead less
Understanding the factors that control T cell responses has been a major focus of immunology. Despite this effort the factors that control T cell development, homeostasis and function are still only incompletely understood. Accordingly we have been studying the TNF-family cytokine BAFF (B cell activation factor of the TNF-family) in relation to T cell behaviour and function. Though BAFF was first described as being critical for B cell development and maturation, a number of lines of evidence ind ....Understanding the factors that control T cell responses has been a major focus of immunology. Despite this effort the factors that control T cell development, homeostasis and function are still only incompletely understood. Accordingly we have been studying the TNF-family cytokine BAFF (B cell activation factor of the TNF-family) in relation to T cell behaviour and function. Though BAFF was first described as being critical for B cell development and maturation, a number of lines of evidence indicate that BAFF may be important in T cell biology. Current studies suggest that BAFF exerts a pro-inflammatory effect upon T cell responses. Surprisingly then, when we examined the role of BAFF upon T cell function in vivo in the context of the allo-immune response, we found that ~60% of BAFF transgenic mice failed to reject a fully-mismatched allograft. Intriguingly, BAFF transgenic mice exhibited an increased number of CD4+ CD25+ Foxp3+ cells in the periphery and in vivo depletion of these CD25+ cells restored the ability of BAFF transgenic mice to reject an allograft. We hypothesize that BAFF plays a potentially powerful anti-inflammatory role in regulating certain T cell dependent immune responses. Our data suggests that BAFF can modulate T cell function by effecting T cell regulation.Read moreRead less