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Pathogen derived Immunomodulatory components as potential mediators of transplant tolerance

Final Report Summary - TOLEROGENIC PAMPS (Pathogen derived Immunomodulatory components as potential mediators of transplant tolerance.)

Pathogenic organisms such as bacteria, viruses and parasitic worms have evolved strategies to actively subvert the host immune system, facilitating their persistence. As a consequence, the identification of specific pathogen derived immunomodulatory molecules has become an intense area of research with a number of such molecules having been found to offer potential as immunotherapeutics in animal models of autoimmune disease and allergy. As there is considerable overlap between the cellular immune responses mounted against 'self' antigens in the case of autoimmunity, and alloantigens in the context of transplantation, we are examining whether immunomodulatory components identified from the excretory secretory (ES) products of the helminth parasite, Fasciola hepatica can alter the generation of an alloimmune response. We have examined the influence of specific immunomodulatory ES components on the generation of alloresponses by examining their specific effects on both antigen presenting cells and T cells.
To date these investigations have led to the identification of specific immunomodulatory components which impact both innate and adaptive immune responses in vitro. These include the identification of a specific novel ES derived component which induces the expression of the immunosuppressive cytokine TGF from dendritic cells (DC) and exhibits profound immunosuppressive effects on both innate DC responses and adaptive T cell activation responses. Furthermore we have established that ES derived components can inhibit the alloresponse in vitro in the context of a mixed leukocyte reaction MLR which has provided the rationale for extending these studies further into in vivo models of transplantation tolerance. The data generated during these studies have addressed and extended Aims1 and Aim 2.1 as outlined in the original proposal, which were to examine the effects of ES components on DC maturation and to determine its impact upon the in vitro alloresponse respectively. We further used an established model of autoimmune disease experimental autoimmune encephalomyelitis (EAE) to examine the immunomodulatory capacity of ES components in vivo. These investigations have determined that ES derived components have the capacity to modulate the immune response in vivo. Having confirmed the capacity of crude ES fractions to induce immune tolerance in vivo, we have chosen to focus further analysis on the identification of specific components of ES which exhibit this immunomodulatory activity. This has led to the identification of 13 novel parasite derived peptides by mass spectrometry which we are currently investigating in a mouse model of graft versus host disease.
Although it is now over half a century since the first successful tissue transplantation in humans, the achievement of operational tolerance, whereby the transplant recipient accepts the allograft without the need for continual immunosuppression, remains elusive. As a result, most transplant patients must undergo chronic treatment with non specific immunosuppressive therapies to prevent graft rejection. Unfortunately such therapies are often accompanied by a range of undesirable side effects, associated with general immune deficiency, such as increased susceptibility to infectious disease and cancer. Therefore a primary focus of transplant immunology has been to define more specific strategies to target the alloresponse without broadly immunocompromising the patient. One approach under intense investigation is to promote an allograft specific immunomodulatory response, which may facilitate graft acceptance while preserving the recipient’s immune response against subsequent unrelated challenge. While a number of parasite derived immunomodulators have been demonstrated to show efficacy in models of autoimmunity, their effects on an allogeneic immune response have not been previously examined. Although differing in terms of the source of antigenic challenge, the immune response to allogeneic cells or tissues, shares many characteristics with the response generated to ‘self’ antigens in cases of autoimmunity. Central to both is the response of activated T cells which require stimulation by DC to induce differentiation towards a pathogenic effector phenotype. Strategies which target this interface between the innate and adaptive immune response have the potential to alter the generation of a pathogenic T cell response either by direct inhibition (immunosuppression) or by altering the qualitative nature of the T cell response toward a more regulatory phenotype. Both such outcomes would be expected to dampen and allogeneic T cell response and promote allograft acceptance or inhibit GVHD after bone marrow transplantation.
Immunomodulatory mechanisms associated with helminth infection are considered to be central to ‘the hygiene hypothesis’ which explains the significantly lower prevalence of autoimmune disorders and allergy in countries where helminth infection is endemic. This has led to an increase in efforts to define specific mediators of immunomodulation associated with helminth infection with a particular emphasis on harnessing their potential as therapies for autoimmunity and allergy. Our proposal, to determine whether these mechanisms can also be exploited to promote transplant tolerance, provides a novel extension of this dynamic and intense area of research.