The intracellular pathway for MHC Class II antigen presentation.

MHC-molekyler kontrollerer de spesifikke immunresponsene mot fremmede antigen. Slike molekyler finnes på celleoverflaten av alle celler, mens immunceller som de hvite blodcellene; B-celler, monocytter, makrofager og dendrittiske celler har flere typer MHC. MHC er delt inn i to klasser, I og II. MHC klasse II-molekylene med fremmed protein som er tatt opp av cellene aktiver T celler. Lasting av antigen på MHC er et resultat av kompliserte cellebiologiske hendelser i endolysosomal systemet. Til tross for omfattende forskning er det fortsatt mye som mangler for å forstå de intracellulære mekanismens for dette. Vi har studert molekylene som samvirker med MHC II og deretter utført et screen der vi har identifisert flere protein interaksjoner som er viktige for å danne en antigen presenterende celle. De viktigste molekylene som ble funnet i screenet var SNARE kompleks som binder til CD74, invariant chain som igjen binder til MHC og fører til dannelse av intraccellulære rom der antigen kan lastes. Vår progresjon i dette prosjektet har ført til en ny forståelse om hvordan antigenpresenterende celler blir dannet fra forløperne, noe som igjen kan brukes til å forbedre immunterapi og vaksinering. Vi har patentert en vaksinevektor som er klar for bruk i immunterapi og har publisert og sent inn artikler til vitenskapelige tidsskrift.

TThis is a basic research project and the aim is to elucidate aspects of the specific immune system. The main outcome from our screen is that the MHC associated CD74 interacts with a set of SNARE molecules. SNAREs are the molecules that decides which membranes that can fuse with each other and direct membrane traffic. That SNAREs interact with CD74 opens up for a theory on how an immune cell is generated. The project has brought the basic field of the trafficking of the immune MHC molecules further. We have developed of a cancer immunotherapy vector based on CD74, and immunization of the patients own dendritic cells. The vector is patented and ready to be tested in patients. Our results are presented in a set of scientific talks and in scientific papers, this will have an impact on the field as a whole with data that can be built on to better understand the function of specific immunity and its importance in the clinic for immune strategies to fight cancer and regulate immunity.

The MHC class II molecules control the specificity of immune responses. These molecules are expressed in the immune system on the cell surface of professional antigen presenting cells like B cells, monocytes, macrophages and dendritic cells. MHC class II molecules present to other immune cells a fragment from proteins that is degraded in the endosomal pathway. This is the result of a complicated series of cell biological events in the endolysosomal system. In spite of extensive research there are still many events including basic ones that are not understood in the regulation of the intracellular pathway in immune cells. Recently our partner in Amsterdam performed an unbiased screen for factors controlling antigen presentation by MHC class II molecules. In this collaboration proposal from three groups, two in Oslo and one in Amsterdam our goal is to use this screen and correlate with other available screening data and microarrays to validate candidates with a clear aim to find additional crucial players in the process of MHC class II antigen presentation. In this process we study the stability and interaction partners with MHC II/invariant chain and aim at crystallizing this multimeric complex. To be able to utilize our targets in modulating immune responses we will use chemical biology to search for chemicals that interact with active sites on the targets controlling this pathway. These drugs could be useful to treat diseases such as autoimmunity, be used in immunotherapy of cancer and in general to regulate the specific immune system.