Rationale for Targeting CD6 as a Treatment for Autoimmune Diseases

CD6 is a 105–130 kDa surface glycoprotein expressed on the majority of T cells and a subset of B cells. The human cd6 gene maps to chromosome 11, and the expression of its protein product is tightly regulated. CD6 mediates cellular adhesion migration across the endothelial and epithelial cells. In addition, it participates in the antigen presentation by B cells and the subsequent proliferation of T cells. CD6 may bind in trans to surface glycoproteins (such as ALCAM and 3A11), or to microbial lipopolysaccharides, and may bind in cis to endogenous ligands (such as CD3 and CD5), and thereby deliver a costimulatory signal. Transinteractions are reinforced during autoimmune diseases (e.g., rheumatoid arthritis (RA), Sjögren's syndrome, and multiple sclerosis) and some cancers. Based on experimental data and on clinical results in RA and psoriasis, we believe that the recent humanized anti-CD6-specific mAb T1h may act as a regulator of the immunological response in addition to its function as an anti-T- and -B cell agent

Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia

<p>Abstract</p> <p>Background</p> <p>We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from <it>Guttiferae </it>trees, display <it>in vitro </it>antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL) and leukemia B cell lines.</p> <p>Results</p> <p>Here, we investigated the <it>in vivo </it>therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (<it>p </it>= 0.0006 and <it>p </it>= 0.0141, respectively). The same treatment of mice which were not xenografted induced no mortality.</p> <p>Conclusion</p> <p>These data show for the first time the <it>in vivo </it>antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.</p

Antitumour effects of single or combined monoclonal antibodies directed against membrane antigens expressed by human B cells leukaemia

Background: The increasing availability of different monoclonal antibodies (mAbs) opens the way to more specific biologic therapy of cancer patients. However, despite the significant success of therapy in breast and ovarian carcinomas with anti-HER2 mAbs as well as in non-Hodkin B cell lymphomas with anti-CD20 mAbs, certain B cell malignancies such as B chronic lymphocytic leukaemia (B-CLL) respond poorly to anti-CD20 mAb, due to the low surface expression of this molecule. Thus, new mAbs adapted to each types of tumour will help to develop personalised mAb treatment. To this aim, we analyse the biological and therapeutic properties of three mAbs directed against the CD5, CD71 or HLA-DR molecules highly expressed on B-CLL cells. Results: The three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as compared to single mAb injection, up to complete inhibition of tumour growth in 100% mice treated with both anti-HLA-DR and anti-CD5. Conclusions: Altogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential

Reduction of radiation dose by application of optimized filtered backprojection algorithm

X-Ray tomography is one of widespread methods of medical diagnostics. Due to its opportunity to visualize inside structure of scanned object it allows to diagnose, for example, cancer cells. Modern medical tomographic setups have lots of advantages such as high resolution, which allows to visualize objects of very small size, high level of reproducibility, which allows to verify obtained results, simplicity of utilization etc. There is certain amount of improvements still can be applied. One of most significant challenges is reducing of radiation dose. Diagnostics of complex structures sometimes requires more time of measurements. That means that dose will increase with time. This work proposes optimized filtered backprojection algorithm as solution for the problem of radiation dose level

Optimisation et limites du transfert de gènes par voie intraveineuse à l'aide de vecteurs non viraux de type lipides cationiques chez la souris Swiss (application à une thérapie génique de la mucoviscidose (doctorat : sciences de la vie et de la santé))

BREST-BU Médecine-Odontologie (290192102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Protection des animaux de laboratoire et aspects pratiques de la recherche sur les animaux.

National audienc

L’expérimentation animale, le point de vue du scientifique

National audienc

Étude fonctionnelle des gènes de "Brucella suis" impliqués dans l'adaptation à la carence en oxygène (rôle dans la pathogénicité)

MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Mesenchymal stromal cells for systemic sclerosis treatment

International audienceSystemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by vasculopathy, dysregulation of innate and adaptive immune responses, and progressive fibrosis. SSc remains an orphan disease, with high morbity and mortality in SSc patients. The mesenchymal stromal cells (MSC) demonstrate in vitro and in vivo pro-angiogenic, immuno-suppressive, and anti-fibrotic properties and appear as a promising stem cell therapy type, that may target the key pathological features of SSc disease. This review aims to summarize acquired knowledge in the field of :1) MSC definition and in vitro and in vivo functional properties, which vary according to the donor type (allogeneic or autologous), the tissue sources (bone marrow, adipose tissue or umbilical cord) or inflammatory micro-environment in the recipient; 2) preclinical studies in various SSc animal models , which showed reduction in skin and lung fibrosis after MSC infusion; 3) first clinical trials in human, with safety and early efficacy results reported in SSc patients or currently tested in several ongoing clinical trials