SummaryMesenchymal stem cell (MSC) therapy has shown promise clinically in graft-versus-host disease and in preclinical animal models of T helper type 1 (Th1)-driven autoimmune diseases, but whether MSCs can be used to treat autoimmune disease in general is unclear. Here, the therapeutic potential of MSCs was tested in the New Zealand black (NZB) ¥ New Zealand white (NZW) F1 (NZB/W) lupus mouse model. The pathogenesis of systemic lupus erythematosus involves abnormal B and T cell activation leading to autoantibody formation. To test whether the immunomodulatory activity of MSCs would inhibit the development of autoimmune responses and provide a therapeutic benefit, NZB/W mice were treated with Balb/c-derived allogeneic MSCs starting before or after disease onset. Systemic MSC administration worsened disease and enhanced anti-double-stranded DNA (dsDNA) autoantibody production. The increase in autoantibody titres was accompanied by an increase in plasma cells in the bone marrow, an increase in glomerular immune complex deposition, more severe kidney pathology, and greater proteinuria. Co-culturing MSCs with plasma cells purified from NZB/W mice led to an increase in immunoglobulin G antibody production, suggesting that MSCs might be augmenting plasma cell survival and function in MSC-treated animals. Our results suggest that MSC therapy may not be beneficial in Th2-type T cell-and B cell-driven diseases such as lupus and highlight the need to understand further the appropriate application of MSC therapy.
The interaction between CD4 and major histocompatibility complex (MHC) class II proteins is critical for the activation of CD4 ؉ T cells, which are involved in transplantation reactions and a number of autoimmune diseases. In this study we have identified a CD4 surface pocket as a functional epitope implicated in CD4-MHC class II interaction and T-cell activation. A computer-based strategy has been used to screen Ϸ150,000 non-peptidic organic compounds in a molecular data base and to identify a group of compounds as ligands of the proposed CD4 surface pocket. These small organic compounds have been shown to specifically block stable CD4-MHC class II binding, and exhibit significant inhibition of immune responses in animal models of autoimmune disease and allograft transplant rejection, suggesting their potential as novel immunosuppressants. This structurebased computer screening approach may have general implications for studying many immunoglobulin-like structures and interactions that share similar structural features. Furthermore, the results from this study have demonstrated that the rational design of small non-peptidic inhibitors of large protein-protein interfaces may indeed be an achievable goal.Protein-protein interactions are critical events in many biological processes. In general, these interactions involve large interfaces with many intermolecular contacts (1, 2). As such, it has long been a great challenge to design small molecular inhibitors of these surfaces in either peptide or more preferably non-peptide form. Recently, it has been suggested that proteins may actually interact through small critical surfacebinding epitopes, as in the cases of the human growth hormone-(3) and the erythropoietin-receptor complexes (4). These findings raise the intriguing possibility that inhibitors of these small binding epitopes may be sufficient for the effective blockade of large protein-protein interfaces. However, the general validity of this hypothesis and its implication for rational drug design remain to be tested and demonstrated in different biological systems. Undoubtedly, the development of a general approach to inhibit protein-protein interactions will have a tremendous impact on the understanding of the structural basis of these interactions and the design of new therapeutic strategies for many human diseases.An important category of protein-protein interactions are those among the immunoglobulin (Ig) superfamily of molecules, which includes a large group of cell surface structures that are characterized by a conserved Ig-like folding (5). The members of the Ig superfamily mediate diverse biological functions in immunity, particularly in cell surface recognition, and thus are attractive targets for drug design studies. In an attempt to better understand the structural basis of Ig superfamily interactions, we have focused on the interaction between the CD4 protein and the major histocompatibility complex (MHC) class II protein. CD4 is a glycoprotein expressed on the surface of helper T cells,...
Recent reports indicate that autoreactive T cells may produce neurotrophic factors capable of mediating repair and regeneration of damaged neurons. By using semiquantitative RT-PCR, we examined gene expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and the trkB BDNF receptor in autoreactive T cells from SWXJ mice immunized with the p104-117 encephalitogen of myelin proteolipid protein (PLP 104-117). We observed antigen-inducible expression of NGF and BDNF, but not NT-3 and trkB, in lymph node cells activated with PLP 104-117. To determine which leukocyte subpopulation expressed neurotrophins, CD4(+), CD8(+), B220(+), CD11b(+), and NK1.1(+) cells were purified from activated primary cultures, and their mRNAs were analyzed. Neurotrophin expression was also measured in CD3(+) T cells purified from mouse CNS during acute onset of experimental autoimmune encephalomyelitis as well as in resting and activated human T cells and B cells purified from peripheral blood of normal subjects. In all cases, we found that neurotrophin expression was confined exclusively to B cells (B220(+)) in both mouse and human. CD3(+), CD4(+), and CD8(+) T cells as well as NK1.1(+) cells and CD11b(+) monocytes and macrophages did not express any detectable BDNF, NGF, NT-3, or trkB under any conditions. Our data indicate that B cells rather than T cells are the predominant if not the only source of leukocyte-derived neurotrophins and as such may provide "protective autoimmunity" in repair and regeneration of the injured nervous system.
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