Five Most Significant Contributions

1) Immune dysregulation in autoimmune diseases and graft-versus-host disease (GVHD): Dr. Prud'homme studied several mouse strains with systemic lupus erythematosus (SLE). These studies demonstrated that the B cell hyperactivity found in SLE can arise through different pathways (J. Exp. Med., 1983, two papers). Later, he studied cytokine abnormalities in lupus prone-mice by quantitative PCR assays he developed, and reported excessive production of interferon-gamma and other cytokines (Mol. Immunol., 1995). He studied gene therapy of this disease with an interferon-gamma- receptor/Ig fusion construct (J. Clin. Invest., 2000, co-author). He has also studied extensively autoimmune (type 1) diabetes in BB rats and NOD mice (J. Exp. Med, 1984; and several subsequent papers).  He was the first to isolate T-cell lines and hybridomas which respond to islet cell antigens (Diabetes 1984). GVHD: He demonstrated exchange of MHC antigens between APCs and responding T cells in vivo in GVHD (J. Exp. Med, 1979), a process now denoted trogocytosis. Later, he studied T-cell anergy and deletion in syngeneic GVHD induced by injecting cyclosporin A (J. Exp. Med, 1992). Recently, he studied homeostatically proliferating T cells in irradiated lymphopenic mice, and showed defective T-cell regulation (published in Blood, 2009).

2) Gene therapy. Dr. Prud'homme developed a method of gene therapy whereby plasmid vectors injected intra-muscularly can direct the production of hormones, cytokines, cytokine inhibitors, or immune costimulatory molecules (papers in J. Immunol., Gene Therapy, Human Gene Therapy, J. Gene Med.). He showed that gene transfer could be greatly enhanced by in vivo electroporation in these experiments (review in Curr. Gene Ther, 2006). These vectors can downregulate or upregulate immune responses in disease models, and he applied this to the treatment of diabetes.      

3) DNA vaccination. Dr. Prud'homme constructed vectors expressing CEA, to induce immunity against this tumour-associated antigen and determine the anti-tumour effects of co-injecting vectors expressing cytokine or other immune-related genes (papers in Gene Therapy, Cancer Gene Therapy, Vaccine). In addition, he developed DNA vaccines against islet-cell autoantigens, which are designed to suppress immune responses in an antigen-specific way and prevent autoimmunity in NOD mice (papers in Human Gene Ther., Mol. Ther. and J. Mol. Med).

4) Drug therapy. He demonstrated that pentoxifylline and rolipram, two phosphodiesterase (PDE) inhibitors, prevent diabetes in NOD mice (papers in Diabetes and Lab. Invest.). He has studied the role of GABA as a natural mediator that stimulates beta islet cell regeneration in diabetic animals, and protects against anti-islet autoimmunity (Proc Natl Acad Sci USA, 2011; Transplantation 2013). Also recently, he has studied a drug denoted tranilast for the therapy of cancer. It prevented breast cancer tumour growth and metastasis (published in Anti-Cancer Drugs). He has identified the aryl hydrocarbon receptor (AHR) as the principal molecular target, and shown that tranilast inhibits cancer stem cells (PLOS ONE, 2010; BBRC 2012; Current Pharmaceutical Design 2012). The finding that the AHR is a molecular target for therapy directed against cancer stem cells is a major discovery.

5) Novel coreceptor for transforming growth factor-beta-1 (TGF-1). Dr. Prud’homme found that neuropilin-1 (Nrp1) is a high affinity receptor for both the active and latent TGF-. This was shown by several assays (co-precipitation, ELISA binding assays, competition with other ligands, blocking antibodies, flow cytometry, etc.). Furthermore, he showed that Nrp1 could activate latent TGF-1 on the membrane of T cells and tumour cells, and contributed to the suppressive activity of regulatory T cells (J. Leukoc. Biol., 2008). Recently, he showed that Nrp1 binds to the signalling TGF-beta receptor (RI, RII, RIII), and enhances signalling in the canonical Smad pathway (Carcinogenesis, 2011; Oncotarget 2012). These studies establish that Nrp1 is a coreceptor for TGF-beta, which is a major discovery in this field. This work is relevant to several processes including angiogenesis, cancer and immunoregulation.