Role Of NK Cell-dendritic Cell Interactions In The Induction Of T Cell Responses Involved In Malarial Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$338,154.00
Summary
Cerebral malaria is a devastating neurological syndrome. Recent data indicate that NK cells are involved in disease induction. NK cell function is controlled by receptors encoded by a genetic region named the Natural Killer Complex (NKC). We showed that the differential expression of NKC genes controls the degree of susceptibility to cerebral malaria. Here we will identify and characterise NKC receptors involved in pathogenesis and the mechanism by which these molecules mediate disease.
The liver is an important organ in terms of immune responses. Owing to its exposure to many antigens, it is required to maintain a form of immune tolerance. This ensures that overt immune responses which would damage the liver do not occur. One means by which tolerance occurs is through silencing killer cells through the regulation of molecules of Major Histocompatibility Complex (MHC). This project will explore the role of a soluble form of MHC which is expressed only in the liver.
Role Of The Natural Killer Complex In The Control Of Murine Malarial Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Natural Killer (NK )cells are an essential arm of the innate immune system. NK cell function is controlled by a series of cell surface receptors encoded within a defined genetic region named the Natural Killer Complex (NKC). This region appears to be highly polymorphic both in mice and humans. It is known that different mouse strains, which differ in the expression of NKC molecules have distinct ability to mount inflammatory responses during infection. In fact, we have previously shown that the ....Natural Killer (NK )cells are an essential arm of the innate immune system. NK cell function is controlled by a series of cell surface receptors encoded within a defined genetic region named the Natural Killer Complex (NKC). This region appears to be highly polymorphic both in mice and humans. It is known that different mouse strains, which differ in the expression of NKC molecules have distinct ability to mount inflammatory responses during infection. In fact, we have previously shown that the differential expression of NKC molecules in mice accounts for the degree of susceptibility to Plasmodium berghei-mediated cerebral malaria, a syndrome that accurately reproduces malarial disease induced by Plasmodium falciparum in humans and that results from an exacerbated pro-inflammatory response to infection. Since the NKC comprises several genes and multi-gene families, the main objective of this proposal is to identify which molecule-s within this genetic region are responsible for the induction of cerebral malaria pathogenesis. Our preliminary results indicate that an activation receptor named Ly49D, which is only expressed on the surface of NK cells from cerebral malaria-susceptible mice, plays a key role in disease-induction. Activation of Ly49D induces NK cells to secrete large amounts of IFN-gamma, a pro-inflammatory cytokine known to mediate cerebral-malaria pathogenesis. We will characterize the immunological function of Ly49D+ NK cells during P. berghei infection and determine whether these cells are the main source of IFN-gamma production. We will also identify the ligand (from parasite or host origin) responsible for the stimulation of this NKC activation receptor during malaria infection. The identification and characterization of these NKC receptors will provide new insights to explain the immunological basis of malarial pathogenesis and could lead to the development of therapeutical approaches designed to prevent severe malarial disease.Read moreRead less
Antigen Presentation, Recognition And The Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$14,927,045.00
Summary
This program focuses on understanding the development of immunity during infection or inflammatory diseases using a broad array of techniques to dissect the function of various immune cell types and to explore the relationship between structure and function of important cell surface molecules. These studies will improve our ability to design new generation vaccines for combating infectious diseases, controlling cancer, or limiting autoimmune or inflammatory diseases.
Structural And Functional Characterisation Of The Killer Cell Immunoglobulin-like Receptor (KIR) Family Of Natural Killer Cell Receptors
Funder
National Health and Medical Research Council
Funding Amount
$348,070.00
Summary
Natural Killer (NK) cells are an important component of the immune response to cancer and infection. This project will define the molecular targets that are recognised by NK cells. This knowledge can then be used to guide in the selection of bone marrow donors in the treatment of leukemias as well as understanding how we fight off infections.