The Role Of Dendritic Cells In Graft-versus-host Disease After Allogeneic Stem Cell Transplantation.
Funder
National Health and Medical Research Council
Funding Amount
$317,633.00
Summary
Allogeneic bone marrow transplantation (BMT) remains the most effect curative treatment for patients with a number of malignant conditions, especially leukemia. Graft-versus-Host Disease (GVHD) ocurrs when the newly transplanted bone marrow (which includes the immune system) recognises the transplant recipient as foreign and mounts an immune attack against patient tissues. GVHD is the major complication of BMT and is responsible for the death of up to half of the patients who receive this proced ....Allogeneic bone marrow transplantation (BMT) remains the most effect curative treatment for patients with a number of malignant conditions, especially leukemia. Graft-versus-Host Disease (GVHD) ocurrs when the newly transplanted bone marrow (which includes the immune system) recognises the transplant recipient as foreign and mounts an immune attack against patient tissues. GVHD is the major complication of BMT and is responsible for the death of up to half of the patients who receive this procedure. Research to date by Dr Hill and colleages has provided substantial detail on how and why this process occurs. This information has led to a number of advances in the field which are already improving patient survival after BMT. This includes a new type of bone marrow transplantation that uses a naturally ocurring growth factor (called a cytokine) to allow the collection of immature bone marrow cells from the blood of transplant donors. The transplantation of these cells rather than bone marrow appears to reduce the chance of dying during BMT and also improves the cure rates from the underlying leukemia. In addition, Dr Hill has developed a novel method for preventing GVHD using different types of naturally ocurring growth factors called cytokine shields that help protect patient tissue from attack by the immune system. It has recently become clear that the immune system is directed by a subtype of white cells called dendritic cells and Professor Hart at the Mater Medical Research Institute has been a pioneer in this field. As initiators of the immune system it is likely that dendritic cells play a pivotal role in GVHD and Dr Hill and Prof Hart at the Mater Medical Research Institute will study DC within the context of Dr Hills newly developed therapies with the aim of further understanding the processes of GVHD. This work will allow manipulation of these cells during BMT in order to improve patient survival.Read moreRead less
Bone marrow transplantation (BMT) is the most effect treatment for a number of conditions, especially leukemia. Graft versus host disease (GVHD) is a complication of BMT and results in the death of up to 50% of transplant recipients. GVHD occurs when the newly transplanted immune system recognizes the recipient as foreign and mounts and immune reponse against the patients tissues. These studies will focus on identifying and understanding the function of the immune cells which drive GVHD.
Immunobiology Of Carbohydrate Antigens In Xenotransplantation
Funder
National Health and Medical Research Council
Funding Amount
$563,554.00
Summary
Xenotransplantation, the transplanting of organs from other species, is now seen as a viable solution to the problem of lack of supply of suitable human donors. The recent production of genetically engineered pigs represented a critical step towards clinical xenotransplantation. However, other sugars still remain that cause rejection. This project examines the consequences of these sugars.
Inhibition Of Alloreactivity By Modulation Of Antigen Presenting Cells
Funder
National Health and Medical Research Council
Funding Amount
$504,097.00
Summary
Bone marrow transplantation (BMT) is the most effect treatment for a number of conditions, especially leukemia. Graft versus host disease (GVHD) is a complication of BMT and results in the death of up to 50% of transplant recipients. GVHD occurs when the newly transplanted immune system recognizes the recipient as foreign and mounts and immune reponse against the patients tissues. These studies will focus on identifying and understanding the function of the immune cells which drive GVHD.
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
Cross-reactive Anti-viral T Cells Mediate Allograft Rejection In Lung Transplantation.
Funder
National Health and Medical Research Council
Funding Amount
$379,563.00
Summary
In solid organ transplantation chronic viral infections can play a major role in causing graft dysfunction and-or loss. This study investigates the role of a specific population of immunological cells. These specific anti-viral immune cells are key controllers of viral infections and have also been implicated in mediating the destruction and-or rejection of a transplanted graft.
Gene Transfer For Corneal Transplantation And Limbal Stem Cell Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$743,463.00
Summary
The cornea is the clear window at the front of the eye. Corneal disease is the second most common reason for blindness in the world. It is sometimes made worse by additional disease affecting the ocular surface. Replacement of a damaged cornea, or of the elements that maintain a normal ocular surface, is possible by transplantation of tissue (either the cornea or the limbus) from a donor eye. The alternative, an artificial cornea, has never yet been reported to function nearly as well as does a ....The cornea is the clear window at the front of the eye. Corneal disease is the second most common reason for blindness in the world. It is sometimes made worse by additional disease affecting the ocular surface. Replacement of a damaged cornea, or of the elements that maintain a normal ocular surface, is possible by transplantation of tissue (either the cornea or the limbus) from a donor eye. The alternative, an artificial cornea, has never yet been reported to function nearly as well as does a successful corneal graft, because the interface between the patient and the prosthesis breaks down and serious problems such as infection are common. Transplantation of the cornea is very successful in some patients but in a sizable subgroup, the graft will fail because of an unwanted immune response. Rejection is the usual cause of a graft failure. Grafts to repair a damaged ocular surface also fail from rejection. Overcoming an unwanted immune response would improve the outcome of corneal transplantation by as much as thirty percent. Overcoming the twin problems of corneal graft rejection and ocular surface disease would make transplantation a feasible option for millions of blind individuals. Novel approaches to abrogation of the immune response to ocular tissue grafts are required, because the many developments in immunosuppression that have improved the survival of other types of transplants have not improved the outcome for grafts in the eye. The immunobiology of the eye is sufficiently different from that of solid organs to demand a different approach. We plan to investigate the use of localised gene transfer to donor eye tissue prior to transplantation, to improve corneal graft and limbal graft outcome.Read moreRead less
Complement Regulation: Protection Against Xenograft Rejection, Ischaemia And Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
Organ transplantation is an accepted solution to treat kidney, heart, lung and liver failure, and is being keenly sought for diabetes treatment. With refined surgical techniques and better controlled immunosuppression, the expected graft survival times are in years. However, the number of individuals who would benefit from transplants exceeds the supply of donor organs, and this number will increase as the benefits of having a transplanted organ increase. There is an active program to research t ....Organ transplantation is an accepted solution to treat kidney, heart, lung and liver failure, and is being keenly sought for diabetes treatment. With refined surgical techniques and better controlled immunosuppression, the expected graft survival times are in years. However, the number of individuals who would benefit from transplants exceeds the supply of donor organs, and this number will increase as the benefits of having a transplanted organ increase. There is an active program to research the possibility of using animal organs (xenografts). This project addresses one of the many issues arising from xenograft transplantation - the rapid activation of the body's complement system, which without treatment results in the very rapid rejection of the graft. In principle this problem can be solved by the development of transgenic donor animals that carry one or more human genes that produce a complement regulating protein, such as CD46 (MCP) or CD55 (DAF). In practice, however, to get successful longterm organ function still requires the selection of the optimal complement regulator or combination of regulators and an understanding of how they function. This research work analyses how CD46 and CD55 function to protect tissues from complement activation, and will result in selection of appropriate transgenes for xenografting. Another aspect of transplantation that is addressed in this proposal is the damage that a graft suffers when the blood supply is temporarily removed during organ harvest and the grafting procedure. This is similar to what occurs during a heart attack when a portion of heart muscle is starved of blood: as the blood flows again through the tissue there is a powerful reaction, again involving complement activation, which is known as reperfusion injury. We have found that perfusing a graft with a soluble form of the CD46 complement regulator provides protection against this damage. The research will measure and optimise this protection.Read moreRead less