Effect Of Ultraviolet Radiation On Development Of Effector And Memory T Cells To Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$498,328.00
Summary
Australia has the highest incidence of skin cancer in the world, due to our lifestyle that involves high levels of exposure to sunlight. Skin cancer, including melanoma can be destroyed by the immune system, but sunlight inhibits immunity, enabling skin tumours to grow. Our aim is to determine how sunlight affects the activation of effector anti-melanoma T cells, and their development into memory T cells, and the dose of sunlight required to have this effect. It is unknown whether ultraviolet ra ....Australia has the highest incidence of skin cancer in the world, due to our lifestyle that involves high levels of exposure to sunlight. Skin cancer, including melanoma can be destroyed by the immune system, but sunlight inhibits immunity, enabling skin tumours to grow. Our aim is to determine how sunlight affects the activation of effector anti-melanoma T cells, and their development into memory T cells, and the dose of sunlight required to have this effect. It is unknown whether ultraviolet radiation in sunlight suppresses the activation of effector cells that mediate rejection of skin tumours, or their development into memory cells, or migration of activated-memory lymphocytes into skin tumours. The number of antigen reactive T cells is a key issue for tumour immunity and the aim of many clinical immunotherapy trials is to boost these to levels that can effectively destroy the tumour. It is important to establish whether low doses of sunlight readily achievable during normal living, or only higher exposures received when sunbaking, inhibit the number of these effector T cells, and their migration into skin tumours. It is important to determine whether there is a relatively safe threshold level of sunlight exposure to be able to give better advice on sunlight doses that can be achieved without causing serious deleterious health effects. Also these levels of sunlight may interfere with immunotherapy trials and therefore need to be determined. An additional outcome will be to determine whether chemopreventative agents that enhance recovery from sunlight induced suppression of skin allergies are also protective for anti-tumour immunity. The establishment of procedures for prevention of suppression of anti-tumour immunity may enhance the number of T cells activated by natural immunity or during immunotherapy, thereby improving immune rejection of melanoma.Read moreRead less
Tolerogenic Dendritic Cells In Kidney Transplantation: Studies In Common Marmoset Monkeys
Funder
National Health and Medical Research Council
Funding Amount
$124,014.00
Summary
Kidney transplantation is the preferred treatment for end-stage kidney disease, but requires immunosuppressive drugs to prevent transplant rejection. However, long-term immunosuppression can have toxic side effects and increase the risks of infection and cancer. This research examines the therapeutic potential of dendritic cells (a specialised immune cell-type) to promote tolerance of the transplant kidney, while enabling maintenance of normal immune function and avoidance of immunosuppression.
Approaches To Allogeneic Chimerism For The Induction Of Transplantation Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
All patients with organ failure who receive a transplant require lifelong immunosuppressive medications to prevent the body from rejecting the foreign tissue. Indefinite immunosuppressive therapy is associated with significant side-effects which include infections and cancers. In addition, long-term loss of the transplants due to slow rejection (chronic rejection) remains high. Achieving a state of immunological tolerance in which transplanted tissue is regarded as self, but reactivity to all ot ....All patients with organ failure who receive a transplant require lifelong immunosuppressive medications to prevent the body from rejecting the foreign tissue. Indefinite immunosuppressive therapy is associated with significant side-effects which include infections and cancers. In addition, long-term loss of the transplants due to slow rejection (chronic rejection) remains high. Achieving a state of immunological tolerance in which transplanted tissue is regarded as self, but reactivity to all other foreign tissues (e.g. harmful viruses, bacteria) remain normal, would solve all these problems. Tolerance would eliminate the need for immunosuppressive medications and prevent rejection of transplanted organs. The production of mixed bone marrow chimerism is a potent method of inducing tolerance. Chimerism is a state in which bone marrow tissue from two genetically different individuals coexists in one person. This can be achieved by bone marrow transplantation from a specific donor, and if chimerism is achieved, the recipient will accept all tissues from the bone marrow donor without the need for ongoing immunosuppressive therapy. This study will attempt to examine the use of different therapeutic reagents (e.g. antibodies alone or antibodies linked to idarubicin, a drug which prevent cells dividing) to develop safe protocols for the production of bone marrow chimerism and tolerance for routine clinical use in humans. The study will also examine different cellular components of the donor bone marrow which may induce tolerance.Read moreRead less
Major Xenoantigens For Neovascularised Porcine Xenografts: The Role Of PERV And MHC In Rejection And Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$504,750.00
Summary
Cross-species transplants (xenografts) of pig organs which use donor pig blood vessels are rejected by antibody which recognises a special target (xenoantigen) on the pig blood vessels; other pig tissue transplants (cellular transplants) which use recipient (not donor pig) blood vessels, are rejected by white blood cells called CD4 T cells. The pig targets recognised by the xenoreactive CD4 T cells are unknown. We plan to identify the major target(s) involved in cellular xenograft rejection. Thi ....Cross-species transplants (xenografts) of pig organs which use donor pig blood vessels are rejected by antibody which recognises a special target (xenoantigen) on the pig blood vessels; other pig tissue transplants (cellular transplants) which use recipient (not donor pig) blood vessels, are rejected by white blood cells called CD4 T cells. The pig targets recognised by the xenoreactive CD4 T cells are unknown. We plan to identify the major target(s) involved in cellular xenograft rejection. This information can then be used to specifically remove or disable only those CD4 T cells capable of recognising the pig tissue and hence facilitate xenograft survival or tolerance without immunosuppression. In this way, the remainder of the CD4 T cell population and immune system is preserved intact. Recent studies have demonstrated that a pig virus (PERV) can be transmitted from pig tissue xenografts to recipient tissues. Our studies have also suggested that the process of xenograft rejection and the immunological recognition of transplant recipient cells infected with the pig virus, are closely related. We plan to investigate this relationship and ascertain whether the immunological destruction of the pig tissue xenograft is largely due to an immune response generated against the pig virus(es) it carries. As an extension of this concept, we will investigate whether long-term xenograft survival (tolerance) is associated with lack of immune reactivity to the pig virus and hence a continual capacity for pig virus to be transmitted to host tissues. This outcome could result in the development of unwanted disease(s) in transplant patients. To prevent these problems, our studies will determine whether it will be essential for such pig virus to be eliminated from the donor pig tissue before transplantation, e.g. by the development of potent anti-viral agents and-or via the development of pig herds that have been genetically engineered to be pig virus (PERV)-deficient.Read moreRead less
Molecular Cloning And Expression Of Cytokine Genes Related To Induction Of Allograft Transplantation Tolerance In Rats
Funder
National Health and Medical Research Council
Funding Amount
$212,371.00
Summary
Cytokines are soluble proteins produced by leucocytes, and in many cases other cell types, which act as chemical communicators between cells, but not as effector molecules in their own right. Most of the cytokines are growth or differentiation factors and they generally act on cells within the haematopoietic system. In this grant application we will focus on the production of cytokines and antibodies to these cytokines, that are likely to be important in organ transplantation tolerance or organ ....Cytokines are soluble proteins produced by leucocytes, and in many cases other cell types, which act as chemical communicators between cells, but not as effector molecules in their own right. Most of the cytokines are growth or differentiation factors and they generally act on cells within the haematopoietic system. In this grant application we will focus on the production of cytokines and antibodies to these cytokines, that are likely to be important in organ transplantation tolerance or organ rejection. We would like to synthesize these cytokines using molecular biological techniques. These biological materials will be used to treat animals and study their biological effect on transplanted graft survival. If the cytokine treatment does prolong graft survival, what is the mechanisms involved in the immune responses will be further studied. Our aim is to develop strategies that couold be applied to help pateints with organ transplants and receive most specific therapies.Read moreRead less