MSC-based therapies in solid organ transplantation.

Immunomodulatory cell therapy as a complement to standard pharmacotherapy represents a novel approach to solid organ allograft acceptance. This methodology may allow for a reduced dose of immunosuppressive drug to be administered and thus attenuate the severe side effects associated with long-term immunosuppression such as drug-related impairment of renal function, increased risk from opportunistic infections and malignancies. Mesenchymal stem cells (MSCs) have been shown to possess both immune modulatory and regenerative properties in vitro and in preclinical models. Encouraging results have been reported from studies examining the safety and efficacy of MSCs as a treatment for acute graft-versus-host disease. MSCs represent a promising candidate cell therapy to supplement immunosuppression in recipients of solid organs, and initial reports on the clinical use of MSCs in kidney transplantation have been recently published (Tan et al. in J Am Med Assoc 307:1169-1177, 2012; Reinders et al. in Stem Cells Transl Med 2:107-111, 2013; Perico et al. in Transpl Int 26:867-878, 2013; Perico et al. in Clin J Am Soc Nephrol 6:412-422, 2011). An area of even greater interest might be the application of MSCs in clinical liver transplantation as graft survival is closely associated with overall patient survival. Here, we present preclinical findings and discuss their possible impact on clinical liver transplantation. Then we discuss clinical studies designed to investigate how MSCs may be distributed and act in solid organ transplantation.

DC-SIGN antagonists, a potential new class of anti-infectives.

DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a type II C-type lectin that functions as an adhesion molecule located on dendritic cells (DCs). It enables some of the functions of DCs, including migration, pathogen recognition, internalisation and processing, and their binding to T cells. HIV-1 has been reported to enter DCs by being bound to DC-SIGN, escaping the normal lytic pathway in DCs' endosomes and avoiding the immune system defence system. A very similar mechanism of survival has been observed for some other pathogens. This makes DC-SIGN a receptor of interest in the design of distinctive anti-infectives that would inhibit DC-SIGN-pathogen interaction by blocking the very first step in pathogen infection. In this review we outline the development of DC-SIGN antagonists, focusing mainly on a glycomimetic approach. Based on the fact that DCSIGN binds mannose- and fucose-based oligo- and polysaccharides, their structural mimics have been designed and proved to inhibit pathogen-DC-SIGN interaction. Furthermore, recent in vitro studies have demonstrated that DC-SIGN antagonists block effectively the transmission of pathogens like HIV-1 and Ebola to CD4+ T cells. Although DC-SIGN has not been validated in vivo as a druggable target yet, we await future DC-SIGN antagonists as a new and highly promising group of novel anti-infectives.

Cathepsin X-mediated beta2 integrin activation results in nanotube outgrowth.

Membrane nanotubes were recently described as a new principle of cell-cell communication enabling complex and specific messaging to distant cells. Calcium fluxes, vesicles, and cell-surface components can all traffic between cells connected by nanotubes. Here we report for the first time the mechanism of membrane nanotube formation in T cells through LFA-1 (CD11a/CD18; alpha(L)beta(2)) integrin activation by the cysteine protease cathepsin X. Cathepsin X is shown to induce persistent LFA-1 activation. Cathepsin X-upregulated T cells exhibit increased homotypic aggregation and polarized, migration-associated morphology in 2D and 3D models, respectively. In these cells, extended uropods are frequently formed, which subsequently elongate to nanotubes connecting T lymphocytes. Our results demonstrate that LFA-1 activation with subsequent cytoskeletal reorganization induces signal transmission through a physically connected network of T lymphocytes for better coordination of their action at various stages of the immune response.

Cathepsin B, cathepsin H, cathepsin X and cystatin C in sera of patients with early-stage and inflammatory breast cancer.

Numerous studies have linked cathepsins and their inhibitor cystatin C to tumor invasion and metastasis. We examined whether cathepsin B, cathepsin H, cathepsin X and cystatin C could be detected in sera from women with early stage or inflammatory breast cancer and whether they correlated with clinicopathological characteristics. Preoperative serum was obtained from 176 patients with early-stage breast cancer (tumor size