Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe combined immunodeficient (SCID) C.B-17-scid/scid (H-2d) strain mice are deficient for T and B lymphocytes and lack all of the immune functions associated with these cell types. Experimental autoimmune encephalomyelitis (EAE) was induced in chimeric SCID mice that had been previously reconstituted with allogeneic mouse or xenogeneic rat hematopoietic stem cells from EAE-susceptible donor strains. Encephalitogenic, myelin Ag-specific, T lymphocytes selected from SJL mice, Lewis rats, or Buffalo rats transferred passive EAE into chimeric SCID mice reconstituted with SJL mouse, Lewis rat, or Buffalo rat hematopoietic cells, respectively. SCID mice reconstituted with Lewis rat hematopoietic tissue and thymus were also susceptible to EAE induced by active immunization with the myelin proteolipid protein synthetic peptide PLP S139-151. T lymphocytes recovered from the spleens of SCID mouse-rat chimeras with EAE proliferated upon in vitro stimulation with myelin Ag presented by APC syngeneic to the transplant donor, and rat T lymphocytes selected in vitro from SCID mouse-rat chimeras with EAE transferred EAE back into naive recipient rats. Thus, the immunodeficiency present in SCID mice can be overcome at least partially by hematopoietic tissue transplantation from allogeneic or xenogeneic donors. Furthermore, allogeneic SJL mouse and xenogeneic Lewis or Buffalo rat myelin Ag-specific T cells can transfer EAE between strains and species, respectively, into recipient SCID mouse chimeras.
 ...
PMID:Induction of experimental autoimmune encephalomyelitis in severe combined immunodeficient mice reconstituted with allogeneic or xenogeneic hematopoietic cells. 809 58

Freshly isolated allogenic pancreatic islets transplanted into the thymus of transiently immunosuppressed rats are not rejected but survive indefinitely while also inducing a state of specific unresponsiveness that permits survival of secondary donor-strain islets transplanted extrathymically. Since freshly isolated pancreatic islets contain intraislet antigen-presenting cells as well as endocrine cells it is unclear which cellular component is primarily responsible for mediating unresponsiveness. We therefore examined the impact of pretransplant in vitro culture (a maneuver which selectively depletes intraislet APCs) on the capacity of islet allografts to induce unresponsiveness after intrathymic implantation. APC-depleted pancreatic islets, which are known to have reduced immunogenicity, survived indefinitely in the thymus of allogeneic hosts whether or not brief immunosuppression was employed, but failed to promote survival of subsequent donor-strain islets transplanted to an extrathymic site. These findings emphasize the central role of APCs in the induction of transplantation tolerance in this model, and are consistent with the established role of this population in the development of T cell tolerance in the thymus.
 ...
PMID:The failure of intrathymic transplantation of nonimmunogenic islet allografts to promote induction of donor-specific unresponsiveness. 815 45

Parent-->F1 bone marrow (BM) chimeras provide a useful model for studying self tolerance induction. When prepared with supralethal irradiation (1300 cGy) and conditioned with anti-T cell antibodies, parent-->F1 BM chimeras are devoid of host BM-derived cells; host H-2 expression is apparent in both the intrathymic and extrathymic environments but is limited to non BM-derived cells. When parent-->F1 chimeras are injected with T cells from normal parental strain mice, the expression of host H-2 antigens on nonprofessional APC might be expected to induce tolerance through induction of clonal anergy. In practice, this does not occur. Instead, a small proportion of the injected T cells is induced to proliferate and differentiate into effector cells. Tolerance is not seen. Similarly, tolerance is not apparent when thymectomized parent-->F1 chimeras are given parental strain thymus grafts. These findings suggest that the expression of host H-2 antigens in the post-thymic environment of chimeras is not intrinsically tolerogenic for mature T cells or recent thymic emigrants. Interestingly, post-thymic tolerance does occur when parental strain T cells differentiate in the endogenous thymus of chimeras. Thus, when mature CD8+ cells are prepared from thymus vs lymph nodes (LN) of parent-->F1 chimeras, tolerance to host class I antigens is more marked in LN than thymus; this applies to cytotoxic T lymphocyte (CTL) precursors, generated by limiting dilution analysis. It would appear therefore that many of the host-reactive CTL precursors generated in the thymus of chimeras undergo tolerance induction (deletion or irreversible inactivation) in the post-thymic environment. We suggest that such tolerance is a reflection of a covert form of tolerance induced in the thymus: intrathymic contact with host antigens on thymic epithelial cells (TEC) in chimeras does not delete typical CTL precursors, but these cells are rendered "semi-tolerant". When cultured in vitro in the presence of lymphokines, the cells are able to recover and differentiate into CTL. In vivo, however, the cells recognize antigen in the periphery in the relative absence of lymphokines and the cells die. Although host class I expression on TEC in chimeras deletes only a small proportion of CTL precursors, contact with TEC induces strong tolerance of CD8+ cells in terms of helper-independent proliferative responses in vitro and induction of lethal graft-versus-host disease in vivo. We postulate that these latter responses are controlled by high-affinity T cells, whereas typical CTL generated in LDA are predominantly low-affinity cells.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Intrathymic and extrathymic tolerance in bone marrow chimeras. 822 65

Deletion of potentially self-reactive T-cell clones during intrathymic development provides an important mechanism of preventing autoreactivity. However, some potentially damaging cells may escape this process. Recent evidence suggests that these cells may be rendered 'anergic', that is, nonresponsive to Ag, in the absence of cell death. Such a mechanism may be particularly important in maintaining tolerance to organ-specific self Ag that are not expressed in the thymus. If so, the emergence of T cells resistant to anergy induction might be expected to result in autoimmune disease. It has previously been shown that anergy can be induced in human T cells in vitro by exposure to specific target peptide or bacterial enterotoxins in the absence of Ag-presenting cells. We have recently defined the antigenic specificity of multiple T-cell clones present at the site of a human organ-specific autoimmune disease, Graves' thyroiditis (Graves disease). In the current work, thyroid-derived T cells recognizing residues 535-551 of the thyroid tissue-specific enzyme, TPO3 have been used to examine whether cells actively involved in the autoimmune process are resistant to anergy induction, as defined by anergy induction with in vitro systems. Two systems were used. First, supraimmunogenic concentrations of peptide 535-551 (up to 1 mg/ml) failed to significantly anergize these T cells in the absence of APC. In addition, the bacterial enterotoxin SED that could stimulate these T cells in the presence of APC, failed to induce anergy when APC were not present. T cells from the peripheral blood of the same individual, in contrast, were anergizable with bacterial enterotoxins, using the same protocol. These results suggest that thyroid-infiltrating autoantigen-reactive T cells are refractory to induction of anergy, and the possibility is raised that this deficiency may be of importance in the development of autoimmunity.
 ...
PMID:T cells involved in human autoimmune disease are resistant to tolerance induction. 833 48

Epidermal Langerhans cells (LC) are a unique subtype of I-A+ dendritic cells able to present Ag for CD4-dependent immune responses. To investigate whether cutaneous Ag presentation is regulated by thymic elements or soluble factors produced by thymus-derived cells, we compared LC function in athymic nude mice and euthymic normal controls. Examination of the ability of LC to present alloantigens to T cell-enriched responder populations, and insulin to an insulin-specific T cell hybridoma, demonstrated that this function is deficient in LC from inbred and outbred strains of congenitally athymic (nu/nu) mice compared with euthymic litter mates. Adoptive transfer of thymic tissue from euthymic to athymic mice reconstituted the ability of LC derived from athymic mice to present alloantigens. To investigate whether an altered local cytokine microenvironment was responsible for the diminished LC function in athymic mice, various cytokines were administered in vivo and in vitro before determination of alloantigen presentation by epidermal cells from athymic and euthymic mice. Continuous intraperitoneal infusion of granulocyte-macrophage colony stimulating factor (GM-CSF) or TNF-alpha, but not IL-1 alpha or IL-2, restored alloantigen presenting ability in athymic LC. In vitro preincubation of LC in GM-CSF or TNF-alpha but not in other cytokines tested also reconstituted alloantigen presentation by LC from athymic mice in most, but not all, of the experiments performed. Furthermore, analysis of cytokine production by epidermal cells in athymic and euthymic mice revealed that epidermal cells from athymic mice produce less GM-CSF and more TNF-alpha, but normal amounts of various other cytokines. However, reconstitution of athymic mice with thymic tissue did not result in normalization of GM-CSF or TNF-alpha production by epidermal cells. These data suggest that LC Ag presenting ability is regulated by thymic factors and that adequate function of cutaneous APC in situ may require the continuous presence of sufficient amounts of cytokines including GM-CSF and TNF-alpha.
 ...
PMID:Deficient antigen presentation by Langerhans cells from athymic (nu/nu) mice. Restoration with thymic transplantation or administration of cytokines. 837 84

A variety of cell types expressing MHC class II molecules is known to function as APC in vitro. We employed the Ig kappa gene enhancer and promoter to target the class II E alpha gene, and thereby I-E, exclusively to B cells to address their APC function in vivo. Although transgenic I-E was expressed on B lymphocytes, we unexpectedly obtained I-E on thymic medullary epithelium but not macrophages and at low frequency on dendritic cells. Using these transgenic mice, we constructed bone marrow irradiation chimeras with I-E expressed only on medullary epithelium, in order to determine the role of this cell type in tolerance by clonal deletion in the thymus. Although it is accepted that bm-derived cells play a primary role in deletion, and thymic epithelium can delete clones to a lesser degree, the role of cortical vs medullary thymic epithelium has not been directly dissected. We demonstrate that medullary epithelium alone can tolerize by partial deletion of I-E-reactive V beta 5+ T cells. These results indicate a role for medullary epithelium in deletion during the later stages of thymic development, and support the notion that positive and negative selection of developing T cells can occur in distinct temporal and anatomic compartments.
 ...
PMID:Clonal deletion of V beta 5+ T cells by transgenic I-E restricted to thymic medullary epithelium. 840 79

A comprehensive model of immunological self tolerance is described which is based on the unique tenet that interactions between T cell antigen receptors (TcR) and specific MHC ligands may vary in efficacy (the ability of an MHC ligand to catalyze TcR-mediated activation). Based on this postulate, two interrelated mechanisms are described to explain how self tolerance is induced among immature thymocytes and mature peripheral T cells, respectively. In the thymus, APC apparently present a diverse array of self MHC ligands (complexes of self peptides and MHC glycoproteins) to clonotypic T cells. According to the first mechanism, immature thymocytes that efficaciously bind specific MHC ligands undergo TcR-mediated activation and programmed cell death whereas those that nonefficaciously bind MHC ligands are not activated and thereby escape negative selection. The latter T cells undergo positive selection and eventually constitute the mature T cell repertoire. This model of thymic selection ensures that interactions of mature T cells with self in peripheral tissues are predominantly nonefficacious. According to the second mechanism, clonotypically diverse T cells and individual APC comprise an integrative unit that measures antigenic complexity of the local environment as a basis to enable or disable immunogenic responses by mature T cells. T cells recognize efficacious MHC ligands (E) via the TcR/CD3 complex but are also able to detect nonefficacious MHC ligands (N) by conserved signal transduction pathways that are initiated upon cell-cell contact with APC. Clonotypic T cells relay E or N signals by conserved feedback pathways back to APC. APC integrate and compare large numbers of E or N signals to derive an E/N ratio.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Immune discrimination of self and nonself: a unified theory for the induction of self tolerance among thymocytes and mature peripheral T cells. 845 73

Murine liver contains alpha beta T cells with intermediate TCR (TCRint) as well as alpha beta T cells with bright TCR. Liver TCRint cells express NK1.1 Ag (NK1+ TCRint) and IL-2 receptor beta chain, both of which are NK cell markers and are not expressed on conventional T cells. Liver NK1+ TCRint cells consist of CD4-8- double negative T cells and CD4+ T cells and have V beta 8+ T cell preponderance. They are dependent on class Ib or CD1 molecules of APC for their development. They can also develop thymus independent manner, because athymic nude mice have this population. These NK1+ TCRint cells in the livers of both euthymic and athymic mice were found to be activated by systemic administration of IL-12 and increased NK1 expression (NK1high TCRint) and cytotoxicity against various NK-sensitive and resistant tumors. Cytotoxicity assays after treatment of IL-12 stimulated hepatic MNC with respective Abs and C revealed that CD4+ NK1high TCRint cells are responsible for IL-12 induced cytotoxicity. Although NK1+ TCRint cells were normally few in the lungs, a significant proportion of NK1high TCRint cells with strong cytotoxicity was also induced in the lung by IL-12. Interestingly, adoptive transfer of IL-12 stimulated hepatic MNC into other mice, which were pre-injected with tumors, inhibits hepatic metastases of EL4 cells and pulmonary metastases of 3LL cells as similarly as IL-12 administration. Transfer experiments after treatment of IL-12 stimulated hepatic MNC with respective Ab and C revealed that depletion of either NK1+ cells, CD3+ cells or CD4+ cells but not CD8+ cells greatly impaired antimetastatic effect in both organs. Thus, CD4+ NK1high TCRint cells are a major antimetastatic population, especially, against hematogenous metastases.
 ...
PMID:[The function and role of extrathymic T cells]. 853 54

Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.
 ...
PMID:Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. 892 Aug 82

We investigated Ag presentation of an extracellular self Ag (C5), which only reaches the thymus via the blood circulation, for negative selection of MHC class II-restricted, C5-specific T cells. Thymic APC were introduced into fetal thymic reaggregation culture with thymocytes from C5-specific TCR transgenic mice to follow the development of C5-specific T cells in the presence or the absence of self Ag presented by various APC. To mimic the physiologic distribution of C5 peptide/MHC class II complexes on thymic APC as closely as possible, they were isolated from thymi of C5+ mice, so that the amount of C5 peptide bound to MHC class II on their surface would reflect the amount of self Ag they have access to and process normally in vivo. This circumvented the problems related to artificially high doses of Ag or peptide in vivo or in vitro, that might obscure physiologic differences such as the capacity to internalize and process Ag. The results show that not only thymic dendritic cells, but also cortical and medullary epithelial cells were able to induce negative selection of C5-specific thymocytes with similar efficiency. In contrast, thymic macrophages were unable to influence the development of C5-specific T cells. Their failure to present exogenous self Ag for negative selection suggests that macrophages concentrate on their primary function in the thymus, the disposal of dying thymocytes.
 ...
PMID:Antigen-presenting cells in the thymus that can negatively select MHC class II-restricted T cells recognizing a circulating self antigen. 899 85


<< Previous 1 2 3 4 5 6 7 8 9 Next >>