Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells.

Acute graft-versus-host disease (aGvHD) is a frequent complication after allogeneic bone marrow/stem cell transplantation (BMT/SCT) induced by co-transplanted alloreactive conventional donor T cells. We previously demonstrated that the adoptive transfer of donor CD4CD25Foxp3 regulatory T cells (Treg) at the time of BMT prevents aGvHD in murine models. Yet, the therapeutic potential of donor Treg for the treatment of established aGvHD has not yet been studied in detail.

Basophils inhibit proliferation of CD4⁺ T cells in autologous and allogeneic mixed lymphocyte reactions and limit disease activity in a murine model of graft versus host disease.

Basophils are known to modulate the phenotype of CD4(+) T cells and to enhance T helper type 2 responses in vitro and in vivo. In this study, we demonstrate that murine basophils inhibit proliferation of CD4(+) T cells in autologous and allogeneic mixed lymphocyte reactions. The inhibition is independent of Fas and MHC class II, but dependent on activation of basophils with subsequent release of interleukin-4 (IL-4) and IL-6.

Endothelial dysfunction and altered mechanical and structural properties of resistance arteries in a murine model of graft-versus-host disease.

A putative involvement of the vasculature seems to play a critical role in the pathophysiology of graft-versus-host disease (GVHD). We aimed to characterize alterations of mesenteric resistance arteries in GVHD in a fully MHC-mismatched model of BALB/c mice conditioned with total body irradiation that underwent transplantation with bone marrow cells and splenocytes from syngeneic (BALB/c) or allogeneic (C57BL/6) donors. After 4 weeks, animals were sacrificed and mesenteric resistance arteries were studied in a pressurized myograph.

Physiologic TLR9-CpG-DNA interaction is essential for the homeostasis of the intestinal immune system.

Background: Cytosine-guanosine dinucleotide (CpG) motifs are immunostimulatory components of bacterial DNA and activators of innate immunity through Toll-like receptor 9 (TLR9). Administration of CpG oligodeoxynucleotides before the onset of experimental colitis prevents intestinal inflammation by enforcement of regulatory mechanisms. It was investigated whether physiologic CpG/TLR9 interactions are critical for the homeostasis of the intestinal immune system.

IL-33 attenuates development and perpetuation of chronic intestinal inflammation.

Background: Interleukin-33 (IL-33) is a member of the IL-1 family. Recent evidence shows the importance of IL-33 in autoimmune and inflammatory diseases. To elucidate its impact on inflammatory bowel disease we studied the effects of exogenous IL-33 during the induction of acute dextran sodium sulfate (DSS)-induced colitis, the induction period of chronic DSS colitis, and after establishment of chronic inflammation.

Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion.

Thymus-derived CD4+ CD25+ regulatory T cells suppress autoreactive CD4+ and CD8+ T cells and thereby protect from autoimmunity. In animal models, adoptive transfer of CD4+ CD25+ regulatory T cells has been shown to prevent and even cure autoimmune diseases as well as pathogenic alloresponses after solid organ and stem-cell transplantations. We recently described methods for the efficient in vitro expansion of human regulatory T cells for clinical applications.

Isolation of CD4+CD25+ regulatory T cells for clinical trials.

The adoptive transfer of donor CD4+CD25+ regulatory T cells has been shown to protect from lethal graft-versus-host disease after allogeneic bone marrow transplantation in murine disease models. Efficient isolation strategies that comply with good manufacturing practice (GMP) guidelines are prerequisites for the clinical application of human CD4+CD25+ regulatory T cells. Here we describe the isolation of CD4+CD25+ T cells with regulatory function from standard leukapheresis products by using a 2-step magnetic cell-separation protocol performed under GMP conditions.