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A novel antigen specific T cell therapy for rheumatoid arthritis

Tuesday 5 May 2009

A novel antigen specific T cell therapy for rheumatoid arthritis

A collaborative study between UMCU (rheumatology) and Faculty of Veterinary Medicine.

T cell therapy is based on the transfer of T cells with a desired immuno-phenotype and specificity. The specificity of a T cell is encoded by its unique T cell receptor. Due to the polymorphic nature of the MHC locus, the diversity of the human T cell repertoire, and the high numbers of antigenic peptides from many tissue-specific or pathogen-derived sources, it is extremely difficult to define a desired TCR sequence in a random patient a priori. However, many autoimmune diseases are associated with T cell recognition of Heat shock protein (HSP)-derived peptides, and also, most autoimmune diseases are strongly associated with an MHC allele. We hypothesize that within populations of human autoimmune disease patients that share an MHC allele, it is possible to define TCR α and β chain sequences that recognize relevant HSP-derived peptides in most or all patients.
During autoimmune diseases, tissue-specific antigens are recognized, as well as more widely distributed antigens. Heat-shock proteins (HSP) are a suitable source of antigens because they are not limited to a specific tissue, are upregulated in many inflamed tissues, and are effective targets of regulatory T cells, as shown in a variety of autoimmune animal model diseases and in humans where the actual disease trigger is unknown or variable (van Eden et al. 2005). We have recently established that the mycobacterial Hsp70-derived peptide B29 and its mammalian homologs mB29a and mB29b bind to HLA-DRB1*04:01, which is strongly associated with rheumatoid arthritis (van Herwijnen et al. 2012). Also, B29 peptides induce a T cell response in mice and humans.
The T cell receptor repertoire for human HLA-DRB1*04:01-restricted, B29-specific peptides is unknown. Defining this TCR repertoire will enable future T cell transfer-based immunotherapy. It is possible that such TCRs are “private”, which means that they are different in each donor, but it is also possible that a “public” TCR with the desired specificity exists (public TCRs are shared among donors that share an MHC allele).
For a successful use of Treg in a therapeutic manner it will be essential to obtain adequate numbers of Tregs with the right T cell specificity. By mere selection and in vitro expansion it remains hard to achieve this. We now propose to transduce regulatory T cells (Treg) with TcRs specific for B29 in the context of DRB1*04:01. With such T cell receptor gene transfer it will be possible to redirect available Treg cell populations to a desired auto-antigen and also, importantly, to switch or fixate their Treg phenotypes (for instance by transducing Foxp3), so that they do not change their suppressive phenotype post-treatment.


For this project the student will:
1) Identify a T cell receptor that recognizes DRB1*04:01-B29, using high throughput TCRβ chain sequencing. To obtain proof of principle for the existence of such public TCRs, we will sequence, bulk-sorted DRB1*04:01-B29 tetramer+ T cells from DRB1*04:01-B29+ donors and determine shared TCRβ chain sequences

2) Identify single, private TCR sequences. Because paired TCR α and β chain sequencing in high throughput is not possible, as an additional approach, the student will generate human T cell clones and sequence single pairs of TCR α and β chains.

Techniques
Cell culture, FACS analysis, Cytokine analysis assays (Luminex,, ELIspot) and Real time PCR, TCRβ chain sequencing, tetramer tracking of CD4 T cells.

Duration
6 or 9 months

Contact: Ildiko van Rhijn (i.vanrhijn@uu.nl) or Willem van Eden (w.vaneden@uu.nl)