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

The development of IL-4 synthesis is a critical step in the regulation of immune responses. Our studies focused on the production of IL-4 by CD4+ T cells taken from mice primed with the Ag keyhole limpet hemocyanin (KLH). In vitro stimulation of such CD4+ T cells with KLH resulted in little or no IL-4 production in the first 24 h of stimulation, indicating that little IL-4 synthesis persists in vivo after immunization. However, IL-4 was generated later at 24 to 96 h of in vitro stimulation, indicating that the potential to produce IL-4 was retained by the KLH-primed CD4+ T cells, but that in vitro maturation of the T cells was required before initiation of IL-4 production. The amount of IL-4 produced in vitro by KLH-primed T cells from BALB/c mice was influenced by several factors. First, stimulation of KLH-primed CD4+ T cells with higher in vitro concentrations of KLH resulted in more IL-4 synthesis, but this was accompanied by more IFN-gamma as well. Second, primed CD4+ T cells from lymph nodes (axillary and popliteal) produced significantly more IL-4 than primed splenic T cells. Third, when primed B cells were utilized to present low concentrations of KLH to the T cells, IL-4 but not IFN-gamma was produced. In contrast, use of splenic adherent cells resulted in IFN-gamma but not IL-4 synthesis. These restricted patterns of lymphokine synthesis, however, were observed only with low concentrations of KLH. Fourth, the amount of IL-4 produced and its regulation by the presence of IFN-gamma differed among mouse strains, in that BALB/c T cells produced much more IL-4 than H-2 identical DBA/2 T cells. Our results characterizing the APC and Ag dose requirements for IL-4 synthesis in KLH-primed T cells from different strains of mice are consistent with previous observations that distinct strains of mice differ in the type of immune response generated against different pathogens, and with the concept that low Ag concentrations preferentially result in high levels of IgE synthesis, which is absolutely dependent on IL-4 production.
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PMID:IL-4 synthesis by in vivo primed keyhole limpet hemocyanin-specific CD4+ T cells. I. Influence of antigen concentration and antigen-presenting cell type. 135 71

Two sets of ((resistant x susceptible) F1----parent) and (parent----F1) chimeric mice were prepared. In the chimeric combinations involving BALB/c and DBA/1 mice, all (F1----F1) chimeras developed arthritis as well as potent anticollagen responses after immunization with collagen, whereas all (F1----BALB/c) and (BALB/c----F1) chimeras induced neither arthritis nor immune responses. This type of F1 T cells could be activated with APC from DBA/1 but not from BALB/c mice. Thus, the failure of the [F1 in equilibrium with BALB/c] chimeras to mount anticollagen responses was due to a defect at the APC level. Another arthritis-resistant strain, C57BL/6, exhibited adequate APC function, but reduced T cell responsiveness, representing an intermediate responder. In the chimeric combinations involving C57BL/6 and DBA/1 mice, (F1----F1) and (C57BL/6----C57BL/6) chimeras developed very high and very low incidence of arthritis, respectively. (C57BL/6----F1) chimeras developed an appreciable incidence of arthritis under conditions in which this group of chimeras generated intermediate levels of anticollagen responses. In contrast, (F1----C57BL/6) chimeras developed low incidence of disease despite induction of strong responses. Moreover, cells from collagen-immunized (F1----C57BL/6) chimeras, when transferred into T cell-depleted B cell mice of F1 or C57BL/6 strain, produced comparable immune responses in both groups but induced much more severe arthritis in F1 than in C57BL/6 recipients. These results indicate that: i) two types of arthritis-resistant strains can be identified, each of which has anticollagen APC defect as a low responder and reduced T cell responsiveness as an intermediate responder and ii) a discrepancy between the degree of anticollagen responses and clinical arthritis is attributed to the differential susceptibility to anticollagen immune responses.
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PMID:Type II collagen-induced murine arthritis: induction of arthritis depends on antigen-presenting cell function as well as susceptibility of host to an anticollagen immune response. 157 34

It has been shown previously that a single intravenous injection of mouse F1 LNC into either parent results in a rapid reduction in the ability of the recipient to generate CTL reactive against donor antigens in an in vitro MLR. The underlying mechanism appears to be the inactivation of host CTL precursors that can recognize donor lymphocytes that have entered the recirculating pool. The donor lymphocytes may be acting as functionally deleting APC, or veto cells. Here, we have injected C57BL/6 (B6) mice with (C57BL/6 x DBA/2) F1 (F1) LNC. The CTL response against donor LNC was maximally reduced by 2 days and stayed reduced for at least 6 weeks, but ultimately recovered to normal levels. The response reduction mechanism remained operative during the period when the response was reduced: Fresh FITC-labeled B6 LNC introduced into B6 recipients of an earlier injection of F1 LNC were as effectively deleted of F1-reactive CTLp as the original host B6 LNC population, the fresh FITC-labelled B6 LNC being separated from host B6 LNC by cell sorting before testing. When B6 mice injected with F1 LNC ultimately recovered their response against F1 donor antigens, reinjection of F1 LNC did not induce a new response reduction. Instead of entering the recirculating pool, the injected F1 cells were rapidly removed by a specific immune process.
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PMID:Rapid and long-term changes to host cytotoxic T lymphocyte precursors reactive to donor antigens caused by intravenous injection of histoincompatible lymphocytes. 163 21

The role of the direct and indirect pathways of alloantigen presentation in the generation of the alloimmune response was dissected using the murine mixed lymphocyte-islet coculture system (MLIC). Stimulator DBA/2J (H-2d) pancreatic islet populations consisted of whole islets (MHC class I+, II+) or FACS-purified beta cells (MHC class I+, II-). Responding C57Bl/6 (H-2b) splenocyte populations were either: (1) untreated; (2) depleted of helper T cells with anti-L3T4 monoclonal antibody plus complement; (3) depleted of cytotoxic T lymphocytes with anti-Lyt2 mAb plus complement; or (4) depleted of antigen-presenting cells by passage through a Sephadex G-10 column. Whole islets were capable of stimulating a significant C57Bl/6 anti-DBA cytotoxic T cell response if the responding population was untreated or treated with complement alone. Depletion of responding splenocytes with either anti-Lyt2 or anti-L3T4 mAb plus complement abrogated the generation of allospecific CTL. If the responding splenocyte population was depleted of APCs, the allo-CTL response against whole islets was decreased, but still significant. If, however, the stimulator population consisted of FACS-purified DBA 2J beta cells, APC-depleted C57Bl 6 splenocytes were incapable of generating any CTL response. Adding responder type (C57Bl/6) APCs back to the microwells restored the capacity for both whole islets and purified beta cells to stimulate a strong allo-CTL response. These data demonstrate that both indirect and direct pathways of alloantigen presentation function in the MLIC.
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PMID:Evidence for direct and indirect pathways in the generation of the alloimmune response against pancreatic islets. 183 68

Presence of the three major pathways (self-Ia restricted, allo-K/D restricted, and allo-Ia restricted pathways) in generating class I-restricted CTL has been reported. The present study was conducted in order to clarify which of the three is the main pathway in mediating tumor allograft rejection. One million EL-4 tumor cells derived from C57BL/6 (B6;H-2b) were inoculated into the various strains of mice that were genetically different from B6. Class I (K/D) Ag-disparate but IA Ag-matched B6.C-H-2bm1 (bm1;Kbm1, IAb, IE-, Db) mice or B10.A (5R) (5R; b, b, k, d) mice could not reject 1 x 10(6) EL-4 tumor cells in spite of the strong generation of CTL against the B6 Ag, suggesting the inability of the self-Ia restricted pathway and the allo-K/D restricted pathway in rejecting tumor allografts. The strains of mice being capable of rejecting EL-4 tumor were disparate from B6 mice in both class I and class II (IA) Ag, suggesting the importance of the allo-Ia restricted pathway in rejecting tumor allografts. To generate CTL against Kb Ag via the allo-Ia restricted pathway in the bm1 mice, 2 x 10(7) B6.H-2bm12 (bm12; b, bm12, -, b) spleen cells were injected into the bm1 mice as a supplementary source of allogeneic APC that possibly raise CTL through CD4+ Th cells of bm1 origin. These bm1 mice became capable of rejecting 1 x 10(6) EL-4 tumor cells. The same was observed in the combination of bm12----B10.A (5R) (b, b, k, d) mice. To further elucidate the role of the class II restricted CD4+ Th cells, anti-CD4 antibody was repeatedly i.v. administered into the C3H/He (C3H; H-2k) or the DBA/2 (DBA; H-2d) mice on days 0, 1, and 4. Injection of anti-CD4 antibody led 1 x 10(6) EL-4 tumor cells to grow and kill the C3H and DBA mice. These results suggest that the main effector CTL pathway involved in tumor allograft rejection is allo-Ia restricted pathway where CD8+ precursor CTL were stimulated by the class II-restricted CD4+ Th cells.
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PMID:Tumor allograft rejection is mainly mediated by CD8+ cytotoxic T lymphocytes stimulated with class I alloantigens in cooperation with CD4+ helper T cells recognizing class II alloantigens. 196 30

Inoculation of P815 tumor cells (DBA/2 origin) into the anterior chamber of eyes of BALB/c mice normally produces anterior chamber-associated immune deviation (ACAID) whereby delayed hypersensitivity (DH) responses to the minor H alloantigens of the tumor cells are suppressed. Based on our previous work showing an association of Langerhans cell infiltration into central cornea with the abrogation of ACAID, we have hypothesized that the induction of ACAID may depend upon the avoidance of local antigen processing within the anterior chamber. In this study, we have examined whether various putative antigen-presenting cells coinjected with allogeneic P815 cells into the anterior chamber could alter the course of the subsequent systemic alloimmune response. BALB/c recipients of intracameral P815 cells admixed with BALB/c spleen cells, B cells, or A20 B lymphoma cells developed ACAID. However, recipients of tumor cells admixed with cutaneous epidermal cells containing LC, and those receiving intracameral P815 cells admixed with purified LC developed vigorous DBA/2-specific delayed hypersensitivity responses. We conclude that avoidance of antigen processing and presentation by specialized APC such as dendritic LC within the anterior chamber is a condition for the induction of ACAID. Since under normal circumstances the anterior chamber is lined by tissues that are devoid of LC and contain very few class II MHC-expressing cells, this immunologically privileged site appears to be designed physiologically to avoid the unique form of local antigen presentation offered by dendritic LC--a condition that favors induction of selective immunologic incompetence.
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PMID:Induction of delayed hypersensitivity to alloantigens coinjected with Langerhans cells into the anterior chamber of the eye. Abrogation of anterior chamber-associated immune deviation. 249

The activation of BALB/c lymphocytes in the mixed lymphocyte reaction to Mls-disparate APC has been shown to encompass up to 20% of the mature resting helper T lymphocyte population. In addition to these overtly Mls-responsive cells, our studies have revealed a second population that respond to the Mls difference of DBA/2 spleen cells in conjunction with the mitogen Con A. This part of the Mls response is therefore latent. As mitogen and Mls-stimulating effect act in synergy, it is likely that both stimuli act on the same cell, and hence the Mls effect can be regarded as a regulatory interaction between APC and Th cell. By use of congenic BALB.Mlsa mice, the regulatory effect has been mapped to the Mls locus. The regulatory influence has also been demonstrated in DBA/2 Th cells (Mlsa) stimulated simultaneously with mitogen and Mls-disparate (Mlsb) APC, consistently causing inhibition of mitogen-induced proliferation in this reverse Mls direction. This antagonistic effect has also been linked to the Mls locus. We conclude that the Mls reaction governed by the a and b alleles is bidirectional, producing synergy with class II-dependent activation signals in the direction of Mlsa----Mlsb, and antagonism in the direction Mlsb----Mlsa. Both the classical Mls and the reverse Mls effects have been demonstrated at the clonal level. These results are in accord with the previously proposed hypothesis that the Mls molecule serves as a down-regulatory stimulus in the activation of Th cells. Mls responses of Mlsb T cells are explained as the consequence of a diminished down-regulation by Mlsa APC. Conversely, the reverse Mls response described here can be considered a consequence of inordinately high down-regulation of the Mlsa T cell responses by Mlsb APC.
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PMID:Bidirectionality of mixed lymphocyte stimulation (Mls) response. Effects of Mlsb stimulator cells on Mlsa helper cells. 296 23

The interaction between lymphocytes and the resident hepatic macrophage, the Kupffer cell (KC), is relevant to the phenomenon of immune tolerance to Ags entering the liver. Tolerance to Ag administered via the portal vein can be prevented by the rare earth lanthanide metal, gadolinium (Gd). Therefore, we studied the ability of OVA-responsive, H-2d-restricted Th1 clones to proliferate in response to KCs from DBA/2J (H-2d) mice that had been injected with either saline (control) or a Gd solution. Whereas control KCs functioned as effective APCs, KCs from Gd-injected mice (GdKC) were incapable of sustaining the proliferative response of the Th1 clone to the 16 mer of OVA (323-339). This lack of proliferation was determined not to be caused by impaired Ag processing, but rather was the result of IFN-gamma-stimulated nitric oxide (NO) release by the APC: 1) In vitro addition of the nitric oxide synthase (NOS) inhibitor NG-methyl-L-arginine (NMMA) restored the ability of the Gd-treated KC to stimulate clone proliferation. 2) Additional of anti-IFN-gamma, but not anti-IL-2 or anti-IL-4, prevented the induction of NOS in the Gd-exposed KC and was associated with clone proliferation. 3) IFN-gamma levels from clone-GdKC-OVA cocultures closely paralleled the nitrite released by GdKCs. 4) Only the addition of rIFN-gamma, and not IL-2 or IL-4, to cultures of purified GdKCs resulted in the release of nitrite. The results of the study suggest an autocrine loop initiated by the interaction of the clone's TCR with the class II MHC molecule presenting processed OVA on the surface of KC. This interaction stimulates the Th1 lymphocyte to release IFN-gamma, which in turn induces NO release by KCs isolated from Gd-injected mice. This release of NO blocks Th1 proliferation. Such a feedback loop may have particular relevance to Ag-specific tolerance, which is not only induced by the administration of Ag into the portal vein, but is also prevented by Gd pretreatment of the recipient animal.
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PMID:Outcome of Kupffer cell antigen presentation to a cloned murine Th1 lymphocyte depends on the inducibility of nitric oxide synthase by IFN-gamma. 752 42

Since Pam 212 cells express low levels of class I major histocompatibility (MHC) antigens, we tested their ability to present alloantigens or minor histocompatibility (mH)/minor lymphocyte stimulatory (mls) antigens in disparate hosts. After subcutaneous injection, Pam 212 cells grew progressive tumors in normal BALB/c mice but were rejected rapidly by naive C3H mice (3 weeks) and slowly by DBA/2 mice (8 weeks). Pam 212 cells (high or low class I MHC expression) induced a strong primary MLR in DBA/2 T cells, but a weak BALB/c T-cell response. In contrast, splenic APC (BALB/c) did not induce an MLR, suggesting that Pam 212 cells represented mH antigens to naive DBA/2 T cells. This MLR was blocked by anti-TCR alpha/beta, anti-class II, and anti-CD4 monoclonal antibodies, but was independent of ICAM-1 and B7. Repeated immunization using IFN-gamma-treated Pam 212 cells induced anti-Pam 212 CTL in DBA/2 mice but not in BALB/c mice. DBA/2 T-cell responses did not appear to be mls (MMTV superantigen)-specific, because Pam 212 cells did not express MMTV mRNA detectable by RT-PCR. Pam 212 cells presented non-lymphoid-associated mH antigens that served as potent stimuli for tumor rejection in mH/mls-disparate hosts, which is similar to tumor rejection mediated by MHC alloantigens.
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PMID:Minor histocompatibility antigen-dependent rejection of Pam 212 epidermoid carcinoma by DBA/2 mice. 754 74

Previous work has shown that a significant proportion of murine splenic dendritic cells (DC) express a high affinity receptor for IL-12, thus accounting for the adjuvanticity of the cytokine when DBA/2 mice are transferred with syngeneic DC exposed in vitro to rIL-12 and an otherwise poorly immunogenic tumor peptide. In DBA/2 mice, splenic DC consist of 90-95% CD8- and 5-10% CD8+ cells. To detect any difference in IL-12 responsiveness among phenotypically distinct DC subtypes, enriched CD8- (>99% pure) and CD8+ ( approximately 80% pure) populations of DC from DBA/2 spleens were assayed for APC function in vivo following exposure to rIL-12 and tumor peptide in vitro. Unlike unfractionated DC, the CD8- fraction was capable of effective presentation of the peptide even when the cells had not been pretreated with IL-12 before peptide pulsing. The addition of as few as 3% CD8+ cells during pulsing blocked in vivo priming by the CD8- fraction. However, pretreatment of CD8- DC with IL-12 before cell mixing and peptide pulsing ablated the inhibitory effect of the CD8+ fraction. CD8-, but not CD8+, DC showed significant message expression for the beta 1 and beta 2 subunits of the IL-12 receptor. These data suggest that a minority population of CD8+ DC, which appeared to secrete IL-10 in vitro, negatively regulates the induction of T cell reactivity by peptide-loaded CD8- DC in DBA/2 mice. However, the CD8- fraction can be primed by IL-12 to overcome the inhibitory effect of the CD8+ subtype.
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PMID:IL-12 acts selectively on CD8 alpha- dendritic cells to enhance presentation of a tumor peptide in vivo. 1047 75


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