TOLEROGENIC PAMPS

Pathogen derived Immunomodulatory components as potential mediators of transplant tolerance

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 Obiettivo del progetto (Objective)

'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 will examine 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 will examine 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. Furthermore we will examine the efficacy of specific ES products in promoting transplant tolerance in models of graft versus host disease and organ transplantation.'

Introduzione (Teaser)

In line with the 'hygiene hypothesis', there are significantly lower levels of autoimmune disorders in countries where helminth infection is endemic. Harnessing the biochemistry behind this phenomenon could be used to promote transplant tolerance.

Descrizione progetto (Article)

Pathogenic organisms from viruses to parasitic worms have evolved elaborate strategies to avoid or even bring down a host's defence immune systems. An EU-funded project has worked on using these highly evolved mechanisms to work in favour of the patient requiring immunotherapy.

Potential for this research avenue is immense in both autoimmunity (immune responses launched against 'self') and alloimmunity. Relevant mainly in the context of transplant rejection, alloimmunity is when antigens are produced as a result of cells from another member of the same species.

The 'Pathogen derived immunomodulatory components as potential mediators of transplant tolerance' (Tolerogenic PAMPS) project is examining whether immunomodulatory excretory and secretory (ES) products from the liver fluke, Fasciola hepatica, can change the generation of alloimmune responses.

The Tolerogenic PAMPS team investigated the effect of ES components on elements of the innate dendritic cell (DC) response and adaptive T cell activation immune responses. The scientists have identified a new specific ES which induces the immunosuppressive cytokine transforming growth factor (TGF) from DCs, linking the innate with the adaptive immune system.

Furthermore, the project scientists also established that ES components can inhibit the alloresponse in vitro in a mixed leucocyte reaction (MLR). Further research is planned to extend the study to in vivo models of transplantation tolerance.

Results so far have been gathered from an existing model of experimental autoimmune encephalomyelitis (EAE). Data has indicated that ES products can downregulate the immune response in vivo and can therefore be used as a basis for future models.

To stop graft rejection, transplant patients have to be treated with non-specific immunosuppressive drugs. Using ES products to dampen the alloimmune response will avoid the resulting predisposition to cancer and infectious diseases.