Unmodified histone proteins such as H3 and H4 are useful for studying epigenetic mechanisms such as histone methylation, histone acetylation, and histone phosphorylation, which occur as a result of the modification to histone...

The induction of hematopoietic mixed chimerism, defined as the coexistence of donor and recipient hematopoietic cells, could be an approach to induce robust central tolerance. This strategy capitalizes on the use of nonmyeloablative hematopoietic stem cell transplantation (HSCT) prior to injection of myogenic stem cells from the donor HST (Parker et al. 2008). In this study two irradiated GRMD dogs with established full or partial chimerism first achieved at 11-26 months, were injected with donor-specific muscle-derived cells. The recipient dogs were transiently immunosuppressed with cyclosporine for 40 days. Local dystro-phin expression, up to 6.5% of normal levels, was sustained for periods up to 24 months post injection. This strategy is promising, as novel developments in the area of nonmyeloablative HSCT are ongoing for other cell-based therapies for benign diseases. Induction of central tolerance by intrathymic injection of viral vectors has been tested in rodents, and offers alternatives ...

In this project we propose to determine the role of candidate G protein-coupled receptors (GPCRs) in enforcing deletion of developing auto-reactive T cells in t...

Most human cancers acquire tens to hundreds of somatic mutations (termed the "tumor mutome") during their development (1). Each of these mutations has the potential to generate one or more novel T-cell antigens (termed "neoepitopes") uniquely specific to each individual patients tumor. Because these neoepitopes are not present in the germline, and are not encountered until after the onset of oncogenesis, repertoires of high-avidity T cells capable of recognizing them may avoid central tolerance and escape deletion in the thymus. For these reasons, numerous investigators have proposed that the tumor mutome provides an attractive source of antigenic targets for developing patient-specific tumor vaccines (2-5).. Because it is already possible to rapidly and comprehensively identify tumor mutations using next-generation DNA- and RNA-sequencing technologies (1), the first technical hurdle for the development of this approach has been overcome. However, it may not be practical to target the full ...

This Podcast features an interview with Vassiliki Boussiotis, senior author of a Research Article published in the 26 June 2012 issue of Science Signaling. Boussiotis discusses her groups investigation of a molecular mechanism by which autoreactive T cells are suppressed in the periphery. Most autoreactive T cells are eliminated by mechanisms of central tolerance in the bone marrow or thymus before they enter the circulation. Autoreactive T cells that escape central tolerance are suppressed or eliminated by mechanisms of peripheral tolerance. Boussiotiss group has described a molecular chain of events downstream of the receptor programmed death-1 (PD-1) that inhibit proliferation of autoreactive T cells.. ...

The term immunogenic cell death (ICD) denotes an immunologically unique type of regulated cell death that enables, rather than suppresses, T cell-driven immune responses that are specific for antigens derived from the dying cells. The ability of ICD to elicit adaptive immunity heavily relies on the immunogenicity of dying cells, implying that such cells must encode and present antigens not covered by central tolerance (antigenicity), and deliver immunostimulatory molecules such as damage-associated molecular patterns and cytokines (adjuvanticity). Moreover, the host immune system must be equipped to detect the antigenicity and adjuvanticity of dying cells. As cancer (but not normal) cells express several antigens not covered by central tolerance, they can be driven into ICD by some therapeutic agents, including (but not limited to) chemotherapeutics of the anthracycline family, oxaliplatin and bortezomib, as well as radiation therapy. In this Trial Watch, we describe current trends in the ...

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in given organism. It contrasts with conventional immune-mediated elimination of foreign antigens (see Immune response). Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced-in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar. Immune tolerance is important for normal physiology. Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.). Deficits in central or peripheral tolerance also cause autoimmune ...

(14) X-Linked SCID IL-2Rγ mutation 6 mo M has thrush, RSV, Pseudomonas aeruginosa No T-cells, low Ig levels Normal B-cell count, did not react to IL-2Rγ Unresponsive to PHA, ConA, PWM, immunizations Complete non-random X- chromosome inactivation Tx: IVIg, ribavirin, TMP-STX, maternal marrow graft SCID: Thrush, persistent cough, intractable diarrhea X-linked is different because B-cell count is normal Mutation in IL-2Rγ (Xq11) is also part of IL-7 involved in T-cell development Successful bone marrow graft yields normal life with Ig-therapy

The postnatal thymus is an efficient microenvironment for T cell specification and differentiation. B cells are also present in the thymus, and have been recently implicated in the central tolerance. In Foxn1lacZmutant mice, which undergo premature thymic involution beginning 1 week after birth, T committed progenitors were progressively reduced, however, thymic B cells started to increase at 1 week and transiently formed a peak at 3-4 weeks. These increased B cells were developed from neonatal derived BM progenitors possessing a high B potential, were originally generated in the thymus. Most of them showed CD19loB220loCD24hiCD43+/−IgM−progenitor phenotype with increased expression of Ly51 but decrease of CD25 accumulating at pre-B-II stage. These B progenitors showed a delayed down-regulation of Lin28b, an impaired up-regulation of Let-7 with an increased expression of Arid3a. However the treatment of these progenitor B cells with Vitamin D3 might up-regulate Let-7 and down-regulate Arid3 ...

Autoimmunity arises from a failure of the immune system to establish or maintain self-tolerance. In the thymus, developing T cells are exposed to self-peptides derived from genetically encoded proteins, and self-reactive T cells are either deleted or develop a regulatory phenotype before venturing into the periphery. Post-translational modification (PTM) of self-peptides in the periphery may lead to the generation of neo-epitopes that are not displayed in the thymus. T cells specific for these modified peptides can bypass central tolerance mechanisms and escape into the periphery where they may ...

Ilan Y, Attavar P, Takahashi M, Davidson A, Horwitz M, Guida J, Chowdhury N Roy, Chowdhury J. Roy Induction of central tolerance by intrathymic inoculation of adenoviral antigens into the host thymus permits long-term gene therapy in Gunn rats. J Clin Invest 1996; 98: 2640-2647 ...

Lee JJ, Rauter I, Garibyan L, Ozcan E, Sannikova T, Dillon SR, Cruz AC, Siegel RM, Bram R, Jabara H, Geha RS. The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function. Blood. 2009 Sep 10; 114(11):2254-62. View abstract ...

Mice. C57BL/6 AireGW/+ mice (17) and C57BL/6 AireGW/+ TRP-1 TCR Tg RAG−/− mice (11) were housed and bred in sterile, specific pathogen-free mouse facilities at the University of North Carolina at Chapel Hill and UCSF. C57BL/6 Aire WT littermate controls were used in all experiments. RAG1−/− mice were purchased from the Jackson Laboratory.. Antibodies and flow cytometry. Anti-CD4 (clone RM4-5), anti-CD3 (clone 145-2c11), anti-Ki67 (clone SolA15), anti-KLRG1 (clone 2F1), anti- granzyme B (clone NGZB), anti-FOXP3 (clone FJK-16s), and anti-CD25 (clone PC61.5) antibodies were purchased from eBioscience. Anti-CD8a (clone 5H10) antibody was purchased from Invitrogen. Intracellular staining for cytokines and FOXP3 were performed as in ref. 11. All samples were run on a Dako CyAn flow cytometer (Beckman-Coulter) and analyzed using FlowJo (TreeStar Inc.).. Isolation of TILs. TILs were isolated as previously described (11). Tumors were dissected and minced before incubation with collagenase type ...

Promising data from trials investigating T/NK-cells modified to express CARs against tumour antigens have generated extensive interest from clinicians, researchers and pharmaceutical companies, leading to broaden the applications of CARs beyond cancer through other pathologies, as autoimmune diseases or allograft rejection [13,14]. Autoimmunity can be broadly separated in two processes: via self-reactive antibodies or "autoantibodies" (produced by plasma cells from the B lymphocyte lineage), and/or via self-reactive T-lymphocytes. This may occur during the processes of selection of those cells during their development (central tolerance), in which negative selection to self-antigens fails, or due to changes in target tissues (break of peripheral tolerance). Between these peripheral autoimmune mechanisms, there are the autorreactivitiy against the so-called "sequestered antigens" (self-antigens present in isolated areas of the organism that are not exposed in normal conditions), that become ...

T cell receptor recognition of peptide Ags presented by class I or class II MHC proteins is a cornerstone of cellular immunity. Recognition of foreign Ags forms the basis for defense against viruses and other pathogens, yet recognition of self Ags can lead to autoimmunity. Although the central tolerance mechanism of negative selection plays a protective role against autoimmunity, the high level of cross-reactivity present within the T cell repertoire can promote autoimmunity if T cells are activated by foreign Ags that share key structural or chemical features with self Ags. This concept of molecular mimicry has been implicated in a number of autoimmune pathologies, including type 1 diabetes, lupus, and multiple sclerosis (1-3).. Previously determined structures of TCRs in complex with self Ags associated with autoimmunity have shown deviations from the binding mode traditionally seen in TCR recognition of foreign Ags. The traditional binding mode, typified by the structure of the αβ A6 TCR ...

Dendritic cells (DCs) are known to regulate immune responses by inducing both central and peripheral tolerance. DCs play a vital role in negative selection of developing thymocytes by deleting T cells with high-affinity for self-peptide-major histocompatibility complexes. In the periphery, DCs mediate peripheral tolerance by promoting regulatory T-cell development, induction of T-cell unresponsiveness, and deletion of activated T cells. We studied whether allogeneic DCs, obtained from bone marrow cultured with either Flt3L (FLDCs) or granulocyte-macrophage colony-stimulating factor (GMDCs), could induce allospecific central and peripheral tolerance after IV injection; B cells were used as a control. The results showed that only FLDCs reached the thymus after injection and that these cells induced both central and peripheral tolerance to donor major histocompatibility complexes. For central tolerance, injection of FLDCs induced antigen-specific clonal deletion of both CD8 and CD4 single-positive

... proteins, show up following the establishment of central tolerance and so are auto-immunogenic so. myoid cells, additional expands its program to review testis morphogenesis. We will also discuss the potential use of this model to study the effects of drugs/environmental toxins on testis morphogenesis, tight junction formation and SCCmyoid cell interactions. [32], co-grafted allogeneic pancreatic islets with syngeneic or allogeneic SC-enriched fractions underneath the kidney capsule of INCB8761 supplier diabetic rats. In this study, 65% of the co-grafted animals remained normoglycemic for over 100 days, while none of the animals receiving islets alone became normoglycemic. However, a short course of immune suppression (cyclosporine for 3 days) was INCB8761 supplier required for the SCs to prolong survival of allogeneic islets. Korbutt [33], extended these results by modifying the SC isolation method and adding a ...