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Results for “Immune cell subtypes”

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PubMed1998

Oral vaccination against tetanus: comparison of the immunogenicities of Salmonella strains expressing fragment C from the nirB and htrA promoters.

We have found the in vivo-regulated nirB promoter (PnirB) to be effective for directing expression of a number of antigens in salmonella in vivo. We wished to determine if other in vivo-regulated promoters have utility for antigen expression in salmonella and to compare the effectiveness of these promoters with that of PnirB. To this end, we have devised a scheme that allows the promoter element of the PnirB-fragment C plasmid pTETnir15 to be swapped with other promoters of interest. We demonstrate the usefulness of this system by replacing PnirB with PhtrA to create plasmid pTEThtrA1. htrA is a stress response gene that is required for virulence of salmonella in mice and survival within macrophages. Expression of fragment C in Salmonella typhimurium BRD509 (aroA aroD) harboring pTEThtrA1 (strain BRD937) correlated with growth temperature in vitro. A comparison was made of the immune responses to fragment C elicited in mice immunized orally with BRD937 or BRD847 (BRD509/pTETnir15) or subcutaneously with purified fragment C plus alhydrogel. High levels of anti-fragment C antibodies that persisted for at least 12 weeks were present in all groups of mice. Vaccination with BRD937 was the most effective means of immunization: the serum immunoglobulin G (IgG), IgA, and IgM anti-fragment C titers were higher in the BRD937-immunized mice throughout the duration of the study than in mice in the other groups. The kinetics of the serum anti-fragment C responses were different in different groups. The response was most rapid in the BRD937 group, with the titers almost at peak levels at 2 weeks postimmunization. Only the mice immunized with BRD937 or BRD847 developed an intestinal IgA response to fragment C. Again, the response was superior in the BRD937 group. The peak of the intestinal response was delayed with respect to the serum response. Analysis of the IgG subtype response to fragment C revealed a dominant IgG2a response in the salmonella-immunized mice, indicating a type 1 helper T-cell response to fragment C, whereas the major subtype in the group parenterally immunized with fragment C plus alhydrogel was IgG1. The IgG1/IgG2a ratio was much higher in sera of BRD937-immunized mice than in sera of BRD847-immunized mice. At 15 to 20 weeks after immunization, the mice immunized with BRD937 or BRD847 were solidly immune to tetanus toxin and salmonella. The immune responses to fragment C seen in mice immunized with BRD937 are the strongest we have observed and indicate that the htrA promoter may be very useful for expressing foreign antigens in salmonella vaccine strains.

Administration, Oral↗

PubMed2026

Distinct spatial immune microenvironment features of different EGFR mutation subtypes in early-stage lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (LUAD), yet their influence on the spatial tumor immune microenvironment (TIME) in early-stage disease remains unclear. We characterized the spatial TIME in 144 treatment-naïve, early-stage LUADs using integrated genomic sequencing and multiplex immunohistochemistry (mIHC). Although EGFR-mutant tumors overall displayed reduced CD8 + T-cell infiltration compared with EGFR-wild-type tumors, substantial heterogeneity was observed among EGFR subtypes. Specifically, L858R and rare-variant subtypes exhibited higher tumor mutational burden, greater CD8 + T-cell density, and enrichment of T-cell-dominant cellular neighborhoods relative to 19del subtype, consistent with a comparatively immune-infiltrated phenotype. In contrast, 19del tumors showed lower T-cell infiltration. TP53 co-mutation was also associated with enhanced CD8 + T-cell infiltration. These cross-sectional findings identify hypothesis-generating spatial immune phenotypes across EGFR-mutant LUAD subtypes; their potential relevance to perioperative treatment selection requires prospective validation in outcome-annotated treatment cohorts.

Humans↗

PubMed1996

Changes in adhesion molecule expression during distinct patterns of immune cell migration in the inflamed lung.

In response to antigen inhalation, immune cells including alveolar macrophages expressing a VIP1 receptor subtype (VIP1R), lymphocytes and leukocytes participate in the inflammatory event, migrating into and from vascular regions in lung tissue of sensitized mice. To analyze these migratory mechanisms of immune cells, we immunohistochemically examined the expression of the following: cellular adhesion molecules, lymphocyte function-associated antigen-1 (LFA-1) very late activation antigen-4 (VLA-4), and the alpha V (alpha v) subunit and their respective ligands, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and fibronectine; the examination was carried out in pulmonary tissue from days 0, 2, 6 and 12 following intratracheal administration of sheep red blood cells (SRBC) as an antigen to previously sensitized mice. Two days following the antigen challenge, VIP1R-positive macrophages strongly expressing the alpha v integrin subunit were found clustered on the endothelial surface and among the aggregates of perivascularly infiltrated leukocytes. On the endothelium of arteries, veins and capillaries, alpha v immunoreactivity was prominently reduced, whereas staining for fibronectin was enhanced more than the prechallenge control level. The blood vessel endothelium was also stained positive for VCAM-1 and ICAM-1, while many of the infiltrating lymphocytes were positive for VLA-4 and LFA-1 immunolabelings. By post-challenge, day 6, delta v integrin subunit immunoreactivity was re-expressed on the blood vessel endothelium and only weakly expressed on VIP1R-positive macrophages, which were in retreat from the leukocyte-aggregating perivascular region and located in the alveoli. VLA-4 bearing lymphocytes conspicuously increased in number among the perivascular leukocytes, while immunoreactivity for LFA-1, VCAM-1, ICAM-1 and fibronectin was unchanged from that for post-challenge day 2. The results indicate that the expression of the alpha v-bearing integrin and its ligand fibronectin drastically changes as pulmonary inflammatory responses. These changes in expression of adhesion molecules during immune response may play an important role in the dynamic regulation of VIP1R-positive macrophage migration in the lung parenchymal compartment.

Animals↗

PubMed1996

Stress-induced changes in blood leukocyte distribution. Role of adrenal steroid hormones.

The numbers and proportions of leukocytes in the blood provide an important representation of the state of activation of the immune system, and of the pattern of distribution of immune cells in the body. We have shown previously that acute stress induces large, rapid, and reversible changes in the distribution of peripheral blood leukocyte subpopulations in the rat. The studies described here specifically investigate the role played by adrenal steroid hormones in mediating stress-induced changes in blood leukocyte distribution. Since adrenal steroids act at two distinct receptor subtypes that show a heterogeneity of expression in immune cells and tissues, the role played by each subtype in mediating changes in leukocyte distribution is also investigated. Cyanoketone, a corticosterone (CORT) synthesis inhibitor, significantly reduced the decrease in lymphocyte numbers observed during stress and significantly enhanced the increase in neutrophil numbers observed after the cessation of stress. Acute administration of aldosterone (a specific type I adrenal steroid receptor agonist) to adrenalectomized animals did not have a significant effect on blood leukocyte numbers. In contrast, acute administration of CORT (the endogenous type I and type II receptor agonist), or RU28362 (a specific type II receptor agonist), to adrenalectomized animals produced changes in leukocyte distribution that were similar to those observed in intact animals during stress. These results suggest that CORT, acting at the type II adrenal steroid receptor, is a major mediator of the stress-induced changes in blood lymphocyte and monocyte distribution.

3-Hydroxysteroid Dehydrogenases↗

PubMed2001

Heterosubtypic immunity to influenza A virus in mice lacking IgA, all Ig, NKT cells, or gamma delta T cells.

The mechanisms of broad cross-protection to influenza viruses of different subtypes, termed heterosubtypic immunity, remain incompletely understood. We used knockout mouse strains to examine the potential for heterosubtypic immunity in mice lacking IgA, all Ig and B cells, NKT cells (CD1 knockout mice), or gamma(delta) T cells. Mice were immunized with live influenza A virus and compared with controls immunized with unrelated influenza B virus. IgA(-/-) mice survived full respiratory tract challenge with heterosubtypic virus that was lethal to controls. IgA(-/-) mice also cleared virus from the nasopharynx and lungs following heterosubtypic challenge limited to the upper respiratory tract, where IgA has been shown to play an important role. Ig(-/-) mice controlled the replication of heterosubtypic challenge virus in the lungs. Acute depletion of CD4+ or CD8+ T cell subsets abrogated this clearance of virus, thus indicating that both CD4+ and CD8+ T cells are required for protection in the absence of Ig. These results in Ig(-/-) mice indicate that CD4+ T cells can function by mechanisms other than providing help to B cells for the generation of Abs. Like wild-type mice, CD1(-/-) mice and gamma(delta) (-/-) mice survived lethal heterosubtypic challenge. Acute depletion of CD4+ and CD8+ cells abrogated heterosubtypic protection in gamma(delta) (-/-) mice, but not B6 controls, suggesting a contribution of gamma(delta) T cells. Our results demonstrate that the Ab and cellular subsets deficient in these knockout mice are not required for heterosubtypic protection, but each may play a role in a multifaceted response that as a whole is more effective than any of its parts.

Administration, Intranasal↗

PubMed2002

Conjunctival T-cell subpopulations in Sjögren's and non-Sjögren's patients with dry eye.

PURPOSE: To examine the conjunctiva of patients with Sjögren's syndrome keratoconjunctivitis sicca (SS-KCS) and non-Sjögren's keratoconjunctivitis sicca (NS-KCS) for evidence of immune-based inflammation. METHODS: Conjunctival biopsy specimens were obtained from 15 patients with SS-KCS and 15 with NS-KCS. Immunohistochemistry was performed on frozen sections to characterize and quantify T-cell subtypes (CD3, CD4, and CD8) and markers of immune activation (major histocompatibility complex [MHC] class II: HLA-DR, HLA-DQ) and inflammation (intercellular adhesion molecule [ICAM]-1). The numbers of cells positive for each marker were counted by two masked observers and averaged. RESULTS: Conjunctival biopsy specimens from patients with SS-KCS or NS-KCS revealed lymphocytic infiltration and increased immunoreactivity for the markers of inflammation and immune activation. The extent of cellular immunoreactivity did not differ significantly between SS-KCS and NS-KCS tissue samples. CONCLUSIONS: The authors' findings indicate that patients with SS-KCS or NS-KCS have conjunctival inflammation manifested by inflammatory cell infiltrates and upregulation of expression in markers of immune activation. Clinical symptoms of KCS may be more dependent on T-cell activation and resultant inflammation than previously believed. In addition to tear substitutes, anti-inflammatory therapeutics should be investigated for the treatment of KCS.

Adult↗

PubMed2006

Runx-dependent regulation of G-protein gamma3 expression in T-cells.

Heterotrimeric G-proteins control diverse biological processes by conveying signals from seven-transmembrane receptors to intracellular effectors. Although their signaling roles were originally ascribed to their GTP-bound alpha-subunits, more recent evidence points to the equally active roles played by their betagamma-dimers. To elucidate the individual contributions of their gamma-subtypes, we used a gene targeting approach to show that mice lacking the gamma3-subtype display a defective T-cell dependent immune response. To identify the cellular basis for this defect, we demonstrated that gamma3-mRNA is strongly induced in activated CD4+ T-cells. To determine the mechanism for this regulated expression, we used several strategies to identify the importance of a Runx consensus sequence element in the first intron of the gamma3 gene and the Runx1 protein. Overall, these data provide the first genetic evidence for the tight regulation and involvement of the G protein gamma3-subtype in mounting an effective immune response in mice.

Animals↗

PubMed1998

Evidence for opioid receptors on cells involved in host defense and the immune system.

Although the role of opiates and opioids in the physiological and pathological function of the immune system is only beginning to be unraveled, converging lines of evidence indicate that the opioid receptors expressed by immune cells are often the same or similar to the neuronal subtypes, particularly delta and kappa. Recent studies also point to the existence of novel opioid receptors and/or binding sites on immune cells that are selective for morphine. Opioids and their receptors, particularly those with high affinity for delta agonists, appear to function in an autocrine/paracrine manner. Thus, opioid peptides generated from immune-derived proenkephalin A act as cytokines, capable of regulating myriad functions of both granulocytes and mononuclear cells. Further identification and characterization of receptors and signal transduction pathways that account for some of the unique properties of opiate binding and immunomodulation (e.g., dose-dependent effects of morphine that occur at exceptionally low concentrations relative to the Kd's of the neuronal mu receptor or the morphine binding site reported on activated human T-cells) represents one of the major research challenges ahead. Elucidating mechanisms, such as these, may provide unique therapeutic opportunities through the application of opioid immunopharmacology to disorders involving immune responses in peripheral organs and the central nervous system.

Humans↗

PubMed1999

Functional role of somatostatin receptors in neuroendocrine and immune cells.

During the last decade the concept of a narrow communication between the immune and classical neuroendocrine systems has been supported by cumulative evidence. One of the common links between the two systems is formed by the production of somatostatin (SS), the presence of SS receptors (SS-R) and the functional effects of SS on both endocrine and immune cells. While in the endocrine system SS-R activation is coupled to mainly inhibitory effects, both inhibitory and stimulatory effects of SS have been demonstrated on the function of immune cells (ie proliferation and secretion). Moreover, in contrast to endocrine cells (ie growth hormone (GH)-secreting pituitary cells) in which SS and its analogues inhibit GH secretion in the nanomolar range in a dose-dependent manner achieving maximal inhibitory effects at higher concentrations, biphasic effects of SS are generally found on the function of immune cells with inhibition at low (nanomolar) concentrations and absence of an effect at higher (micromolar) concentrations. Neuroendocrine cells often express multiple SS-R subtypes, which may be linked to specific functions. Scarce information is available so far on the SS-R subtype expression pattern as well as on the second messenger systems linked to SS-R activation in human lymphoid cells. The recent development of novel SS-R subtype-selective SS analogues will be helpful in unravelling the functional roles of the individual SS-R subtypes in SS-R-expressing human neuroendocrine and immune cells.

Animals↗

PubMed2003

The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12.

The recruitment of selected dendritic cell (DC) subtypes conditions the class of the immune response. Here we show that the migration of human plasmacytoid DCs (pDCs), the blood natural interferon alpha-producing cells, is induced upon the collective action of inducible and constitutive chemokines. Despite expression of very high levels of CXCR3, pDCs do not respond efficiently to CXCR3 ligands. However, they migrate in response to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 and CXCR3 ligands synergize with SDF-1/CXCL12 to induce pDC migration. This synergy reflects a sensitizing effect of CXCR3 ligands, which, independently of a gradient and chemoattraction, decrease by 20-50-fold the threshold of sensitivity to SDF-1/CXCL12. Thus, the ability of the constitutive chemokine SDF-1/CXCL12 to induce pDC recruitment might be controlled by CXCR3 ligands released during inflammation such as in virus infection. SDF-1/CXCL12 and the CXCR3 ligands Mig/CXCL9 and ITAC/CXCL1 display adjacent expression both in secondary lymphoid organs and in inflamed epithelium from virus-induced pathologic lesions. Because pDCs express both the lymph node homing molecule l-selectin and the cutaneous homing molecule cutaneous lymphocyte antigen, the cooperation between inducible CXCR3 ligands and constitutive SDF-1/CXCL12 may regulate recruitment of pDCs either in lymph nodes or at peripheral sites of inflammation.

Antigens, CD↗

PubMed2005

Lack of effect of repeated suberythemal ultraviolet-B exposures on human blood dendritic subtypes.

BACKGROUND/PURPOSE: Dendritic cells (DC) play a major role in the afferent immune response. They are found as a minor cell population in the blood as three main subtypes that can be distinguished phenotypically: plasmacytoid DC (PDC), and myeloid DC1 and 2 (MDC1 and 2). The aim of the study was to examine the effect of repeated whole-body suberythemal ultraviolet (UV) B irradiation on the percentages of DC subsets in the blood and skin, and to test for photoadaptation by the subsequent administration of a local erythemal UV dose. METHODS: Thirty subjects in each group were irradiated with either 0.7 personal minimal erythema dose (MED) UVB daily for 10 days (whole body), or for the 10 days followed by a single three MED UVB exposure of a local body site, or with the single three MED UVB exposure of a local body site only. Blood was collected before and after the exposures and the percentage of DC and DC subtypes assessed by flow cytometry. Skin biopsies were collected at the same times, and the number and position of the DC subsets examined by immunofluorescent microscopy. RESULTS: The whole-body repeated UVB irradiations did not result in a change in the blood DC (BDC) or the subsets percentages in the blood, except that there was a small but significant rise in the percentage of the MDC2 subset. No alteration occurred following the local erythemal UVB exposure. The total number of BDC in the skin was small, with the PDC being located mainly in the dermis and the myeloid subtypes mainly in the epidermis. No change in cutaneous numbers or distribution was revealed following the irradiation protocols. CONCLUSIONS: Repeated whole-body suberythemal UVB irradiation does not cause a change in BDC or BDC subsets in the blood or skin, except for a small increase in the percentage of MDC2 in the blood. Local erythemal UVB irradiation does not alter the BDC subsets in blood or skin.

Adult↗

PubMed2006

Innate immune dysfunction in HIV infection: effect of HIV envelope-NK cell interactions.

We have previously described a number of NK cell dysfunctions in HIV-viremic individuals. In the present study, we performed DNA microarray analysis followed by phenotypic and functional characterization in an effort to investigate which HIV envelope glycoproteins (gp120) affect the physiologic functions of NK cells. Upon treatment of NK cells with HIV gp120, DNA microarray analyses indicated up-regulation of several categories of genes that are associated with apoptosis, suppression of both cellular proliferation and survival, as well as down-regulation of genes that play a vital role in cell proliferation, innate immune defense mechanism, and cell survival. Both subtypes of gp120 suppressed NK cell cytotoxicity, proliferation, and the ability to secrete IFN-gamma. NK cells exposed to X4-subtype HIV gp120 showed a significant decrease in the levels of CC chemokines, while exposure to R5-subtype HIV gp120 had minimal effect. Extended exposure to HIV gp120 resulted in apoptosis of NK cells, further validating the microarray data. Our data demonstrate that exposure of NK cells to HIV envelope proteins results in profound cellular abnormalities at the level of gene expression as well as generic cell functions. These findings are likely to be a consequence of a direct HIV gp120-mediated effect on NK cells. Identification of specific surface receptors on NK cells that interact with HIV envelope proteins might explain how HIV is capable of circumventing innate immune defense mechanisms and establishing infection in susceptible individuals.

Apoptosis↗

PubMed1977

Cell-mediated immunity after oral immunization with ribonucleic acid-protein fractions of Vibrio cholerae L-form lysates.

Oral administration of a single dose of ribonucleic acid-protein fraction of lysates of Vibrio cholerae subtype Ogawa L-forms induced an increase in cell-mediated immunity in rabbits. This was demonstrated by an increase in leukocyte migration inhibition in peripheral blood leukocytes, in macrophages migration inhibition, and in microbicidal activity against Listeria monocytogenes in peritoneal macrophages obtained from orally immunized rabbits. Increased cell-mediated immunity was induced mainly with V. cholerae Ogawa and ribonucleic acid-protein fractions. It appeared in 20 days and persisted for at least 90 days.

Administration, Oral↗

PubMed2026

CCT2 defines a highly cisplatin-resistant and poor-prognosis subtype of lung adenocarcinoma.

Cisplatin-based chemotherapy is a standard treatment for lung adenocarcinoma (LUAD), yet acquired cisplatin resistance remains a marked cause of treatment failure. The molecular mechanisms driving cisplatin resistance in LUAD have not been fully elucidated. The present study integrated bulk transcriptomic data, genomic mutation profiles and single-cell RNA sequencing data to systematically investigate cisplatin resistance in LUAD. Resistance-associated genes were identified through differential expression, survival analysis and database integration. Unsupervised clustering was used to define cisplatin resistance-associated subtypes. Functional characteristics were explored using pathway enrichment, immune infiltration, tumor mutation burden and weighted gene co-expression network analysis. A machine learning framework incorporating 101 algorithms was applied to identify key genes and construct a prognostic model. Single-cell analyses and in vitro experiments were performed to validate the biological role of the core gene. Molecular docking and molecular dynamics simulations were conducted to identify potential therapeutic compounds. A total of two molecular subtypes with distinct cisplatin resistance levels and prognostic outcomes were identified. The high-resistance subtype exhibited enhanced cell cycle activity, DNA repair signaling and immune heterogeneity. Machine learning analysis revealed a five-gene signature, with chaperonin-containing TCP1 subunit 2 (CCT2) emerging as a key regulator of cisplatin resistance. Single-cell analyses showed that CCT2 was predominantly enriched in resistant epithelial cell subpopulations. Functional experiments demonstrated that CCT2 knockdown significantly inhibited cell proliferation and enhanced cisplatin sensitivity in LUAD cell lines. A number of candidate compounds targeting CCT2 exhibited stable binding in silico. The present findings identified CCT2 as a key mediator of cisplatin resistance in LUAD and provided potential therapeutic strategies to overcome chemotherapy resistance.

chaperonin-containing TCP-1 subunit 2↗

PubMed1994

Analysis of overlapping T- and B-cell antigenic sites on rubella virus E1 envelope protein. Influence of HLA-DR4 polymorphism on T-cell clonal recognition.

A CTL antigenic site located between residues 273 and 291 of the E1 envelope protein of RV was identified by 51Cr-release assays employing SPs. Two E1-specific CTL clones were examined for immune recognition of RV wild-type and attenuated vaccine strains and recombinant E1 protein. The exact sequence (273-284) recognized by both clones was delineated by using truncated and overlapping SPs covering these residues. The defined T-cell site overlapped almost completely with a virus neutralizing antibody-binding site previously identified with mouse monoclonal and human antibodies. A series of single aa-substituted SP analogues of E1(273-284) was used to define residues critical for T-cell recognition. Using EBV-BL displaying different HLA-DR haplotypes and -DR4 subtypes as targets to determine MHC class II restriction elements, immune recognition by both T-cell clones was shown to be associated with HLA-DR4. Three HLA-DR4 subtypes (DR4Dw13A, DR4Dw13B, and DR4KT2) sharing a common residue, glutamic acid at position 74 in their beta 1 chains, were able to present SP E1(273-284) to the T-cell clones.

Amino Acid Sequence↗

PubMed2000

A mucosal vaccine against diphtheria: formulation of cross reacting material (CRM(197)) of diphtheria toxin with chitosan enhances local and systemic antibody and Th2 responses following nasal delivery.

The development of new generation vaccines against diphtheria is dependent on the identification of antigens and routes of immunization that are capable of stimulating immune responses similar to, or greater than, those obtained with the parenterally-delivered toxoid vaccine, while reducing the adverse effects that have been associated with the traditional vaccine. In this study, we examined the cellular and humoral immune responses in mice generated after both parenteral and mucosal immunizations with cross-reacting material (CRM(197)) of diphtheria toxin. We found that both native and mildly formaldehyde-treated CRM(197) and conventional diphtheria toxoid (DT) induced mixed Th1/Th2 responses and similar levels of anti-DT serum IgG following parenteral immunization. In contrast, CRM(197) preparations were poorly immunogenic when administered intranasally in solution. However, formulation of the antigens with chitosan significantly enhanced their immunogenicity, inducing high levels of antigen-specific IgG, secretory IgA, toxin-neutralizing antibodies and T cell responses, predominately of Th2 subtype. Furthermore, intranasal immunization with CRM(197) and chitosan induced protective antibodies against the toxin in a guinea pig passive challenge model. We also found that priming parenterally with DT in alum and boosting intranasally with CRM(197) was a very effective method of immunization in mice, capable of inducing high levels of anti-DT IgG and neutralizing antibodies in the serum and secretory IgA in the respiratory tract. Our findings suggest that boosting intranasally with CRM(197) antigen may be very effective in adolescents or adults who have previously been parenterally immunized with a conventional diphtheria toxoid vaccine.

Administration, Intranasal↗

PubMed1989

Lymphocyte immunophenotyping in an elderly population: age, sex and medication effects--a flow cytometry study.

Flow cytometry studies of 179 individuals aged 55-95 years reveal correlations of various hematological and immune cell measures (quantification of leukocytes, leukocyte subtypes, platelets, and erythrocytes) with age, sex, common medications (aspirin, ulcer therapy, estrogen replacement therapy), and health history variables (minor arthritis, allergy, smoking, stress and exercise). Possible reasons for some of these findings are discussed.

Age Factors↗

PubMedDate not supplied

Prolongation of heterotopic heart allograft survival by portal venous injection of alloantigen: the role of hepatic nonparenchymal cells.

The induction of immune hyporesponsiveness in transplantation is a complex interaction between the immune system and the alloantigen. The route by which an antigen is introduced to the immune system plays an important role in the immune response. Antigen delivered via the portal circulation has the ability to induce T-cell hyporesponsiveness. In this study we examined the mechanism responsible for the induction of hyporesponsiveness by assessing immune response following portal vein (pv) injection of donor alloantigen. C57B1/6 mice were immunized via pv with splenic mononuclear cells (SMNC) from BALB/c mice. The recipient immune response was assessed in vivo by murine heterotopic heart transplant survival. SMNC and hepatic nonparenchymal cells (NPC) were isolated from pv immunized animals and used as regulatory cells in a one-way mixed lymphocyte culture (MLC) as a measure of in vitro recipient responder SMNC proliferation. Survival of murine heterotopic heart transplants was prolonged following pv injection of alloantigen (p < .04 compared to nonimmunized or systemically immunized mice). Stimulation of responder SMNCs isolated from pv immunized mice resulted in an antigen-specific hyporesponsiveness (p < .05 compared with nonimmunized or systemically immunized mice). Cocultures of responder SMNCs from nonimmunized (naive) mice with hepatic NPC from previously pv immunized mice resulted in attenuation of T-cell proliferation in MLR following stimulation with donor alloantigen (p < .05 compared to coculture with NPC from nonimmunized mice or SMNC from pv immunized mice). These data would suggest that the hepatic NPC plays an important role in the regulation of the immune response. With further identification of cell subtypes responsible for induction of hyporesponsiveness, future therapies may be directed at these specific targets, thereby minimizing the harmful side effects of current immunosuppressive therapies.

Animals↗