Biomedical subjects

S O Sharrow

Publications and source records attributed to S O Sharrow.

At least 73 records · Page 4Linked to original sources

PubMed1987

Interstitial pneumonitis during murine cytomegalovirus infection and graft-versus-host reaction. Characterization of bronchoalveolar lavage cells.

Acute murine cytomegalovirus (MCMV) infection alters the course of graft-vs-host (GVH) disease involving major histocompatibility (MHC) antigens and induces interstitial pneumonitis. F1 (B10 x B10.BR) mice given 20 x 10(6) B10.BR spleen cells and MCMV (1 x 10(5) plaque-forming units [PFU]) develop severe, diffuse pneumonitis not seen with either MCMV or GVH alone. As one index of the host immune processes operating in the lungs during MCMV/GVH pneumonitis, we examined the types of cells recovered from the lung by bronchoalveolar lavage (BAL) during pneumonitis. During MCMV/GVH pneumonitis, the total cells recovered significantly increased, due primarily to an influx of Thy 1.2 lymphocytes. Characterization of cells using multiparameter flow cytometric analysis revealed that greater than 80% of all BAL cells were Thy 1.2-positive lymphocytes of donor origin. In addition, donor Thy 1.2-positive cells were of both the L3T4+ (43% of BAL cells) and Lyt 2+ (38% of BAL cells) phenotype. Thus, MCMV infection during GVH to MHC antigens induces interstitial pneumonitis, characterized by an influx of T lymphocytes (both helper and suppressor/cytotoxic) from the donor. The antigenic specificity of these cells is not known.

Animals↗

PubMed1986

Interleukin 2 receptor expression in unstimulated murine splenic T cells. Localization to L3T4+ cells and regulation by non-H-2-linked genes.

The present study reports the surprising observation that IL-2-R+ cells can be detected in fresh, unstimulated, murine spleen T cells from unimmunized mice by flow cytometry using the monoclonal anti-receptor antibody 7D4. Also, unexpectedly, these cells were found exclusively in the L3T4+Lyt-2- population by two-color fluorescence, in contrast to receptor+ cells after stimulation, in which both L3T4+Lyt-2- and Lyt-2+L3T4- cells were found. The fraction of splenic T cells bearing IL-2-R reproducibly varies twofold under non-H-2-linked genetic control, with high expression in DBA/2 and BALB/c (approximately 6-7%) and low expression in B10.D2 and C57BL/6 (3%). This correlates quantitatively with a greater responsiveness of the DBA/2 and BALB/c splenic T cells to high doses of IL-2, compared with B10.D2 T cells; twice as many B10.D2 T cells as DBA/2 T cells were required to get the same response. Studies with 23 B X D RI strains revealed that the level of IL-2-R+ cells in unstimulated spleen cells was regulated by multiple genes, very likely including at least one gene on chromosome 7, near the HBB locus. The mapping makes novel use of nonparametric (Smirnov) statistics, which we suggest may be of general usefulness in similar analyses of RI strains.

Animals↗

PubMed1986

Qa alloantigen expression on functional T lymphocytes from spleen and thymus.

The cell-surface expression of the class I alloantigen Qa-2 was analyzed on resting and activated spleen and thymus cells using cytotoxic elimination and immunofluorescence and flow cytometry. Spleen cells activated by mitogens or alloantigen were homogeneously positive for cell surface Qa-2, but activated splenic T cells expressed only about one-third as much Qa-2 per cell as did nonstimulated T cells. These data correlated with the ability to perform cytotoxic elimination with Qa-2-specific monoclonal antibodies (mAbs) in that cytotoxic T lymphocyte (CTL) activity was completely abrogated by pretreatment of spleen cells prior to in vitro culture but was only partially eliminated by treatment of CTL effectors. Qa-2-positive cells constituted only a small subpopulation of fresh normal thymocytes, but were enriched (greater than 40% positive) among cortisone-resistant thymocytes (CRT). These Qa-2-positive CRT contained mature thymocytes as defined by Ly phenotype Ly-2-, Ly-1hi. When normal thymocytes were treated with Qa-2-specific mAb and complement prior to in vitro sensitization for generation of allogeneic CTL, CTL activity was completely abrogated despite the fact that the fraction of cells eliminated were undetectable as assessed by cell recovery. CTL effectors from alloantigen-stimulated thymocytes were also susceptible to cytotoxic elimination with Qa-2-specific mAb. These data suggest that the Qa-2 molecule may serve not only as a marker on resting and activated peripheral T cells, but also as a unique marker for functionally mature T cells in the thymus.

Animals↗

PubMed1986

Ia+ murine epidermal Langerhans cells are deficient in surface expression of the class I major histocompatibility complex.

Murine epidermal Langerhans cells were analyzed with fluorescence microscopy and multicolor flow cytometry for the surface expression of major histocompatibility complex (MHC) class I and class II antigens. Langerhans cells of H-2k haplotype were identified in situ or in epidermal-cell suspensions by their surface expression of the MHC class II determinants I-Ak and I-Ek. More than 90% of class II-positive Langerhans cells in epidermal-cell suspensions expressed no or barely detectable amounts of MHC class I antigens. Quantitation by flow cytometry revealed that H-2k Langerhans cells expressed only 1.6-3.3% as much H-2Kk as did class II-negative keratinocytes in the same epidermal-cell suspensions. By fluorescence microscopy, class I MHC antigens were not detectable on Langerhans cells in situ when analyzed on sheets of intact epidermis. The deficient expression of class I MHC permitted highly purified Langerhans cell populations to be isolated from epidermal cell suspensions by treatment with anti-class I MHC monoclonal antibody and complement. It is likely that the uniquely low cell-surface expression of class I MHC antigen by Langerhans cells has relevance to both immune responses in the skin as well as to mechanisms of skin allograft rejection. In addition, it is conceivable that regulation of class I MHC expression on antigen-presenting cells in general is an important but hitherto unrecognized mechanism of immune regulation.

Animals↗

PubMed1986

Culture and characterization of murine dendritic Thy-1+ epidermal cells.

Although numerous advances have been made in characterizing the phenotype, ontogeny, ultrastructure, and cytochemistry of the murine Thy-1+ dendritic epidermal cell (Thy-1+ EC), elucidation of its functional qualities has been hampered by the difficulty in preparing pure populations of these cells. We therefore sought to obtain expanded, purified populations of Thy-1+ EC using culture techniques. Since Thy-1+ EC are bone marrow-derived, density gradient enriched populations of freshly harvested epidermal cells (FH-EC) were placed in culture under conditions known or suspected to promote mitogenesis among leukocyte subsets. FH-EC prepared from truncal skin of C3H/HeN mice (Thy-1.2+) were cultured at 37 degrees C in 5% CO2 in complete medium (CM) of Eagle's Hanks' amino acid with 10% fetal calf serum, nutrients, and antibiotics at 10(6) FH-EC/well in 24-well culture plates. CM was supplemented with one or more of the following: concanavalin A (Con-A), interleukin-1/epidermal cell-derived thymocyte-activating factor (IL-1/ETAF), IL-2, IL-3, gamma interferon, indomethacin (IM), and anti-Thy-1.2 antibody. Media with appropriate supplements were changed every 2-3 days. Freshly isolated, enriched FH-EC contained 7-20% Thy-1+ EC (defined as brightly fluorescing cells readily distinguishable from weakly fluorescing keratinocytes), which also stained with antibodies directed against asialo GM1, Ly 5.1, and vimentin but did not stain with antibodies to other T cell-, B cell- or macrophage phenotypic markers. Analysis of 10 separate cultures revealed a 3- to 10-fold expansion of nonkeratinocyte Thy-1+ cells after 21 +/- 4 days in culture in CM supplemented with Con-A and IM, and 70-100% of viable cells after expansion were Thy-1+. Phenotypic analysis of expanded cells revealed the emergence in 10 separate cultures of one of two mutually exclusive distinct populations: one Thy-1+, asialo GM1+, L3T4- (natural killer phenotype) and the other Thy-1+, asialo GM1-, L3T4+ (T helper phenotype). Experiments designed to explain the emergence of an L3T4+ population suggest that phenotypic modulation occurred in vitro.

Animals↗

PubMed1985

Expression and T cell recognition of hybrid antigens with amino-terminal domains encoded by Qa-2 region of major histocompatibility complex and carboxyl termini of transplantation antigens.

Coding potential of the Q6 gene from the Qa-2a region of BALB/c Crgl mice was analyzed by a combination of hybrid class I gene construction and DNA-mediated gene transfer. Recombinant genes were created by exon shuffling of the 5' coding region of the Q6 gene and the 3' coding region of a gene encoding a transplantation antigen (Kd, Dd, or Ld), or the inverse. Some of these hybrid class I genes were expressed in the transfected mouse fibroblasts (L cells). The hybrid class I molecules encoded by the 5' end of the Q6 gene and the 3' end of the Ld gene precipitated as 45,000 mol wt molecules associated with beta 2-microglobulin. The expression of the hybrid proteins indicates that 926 basepairs of the 5' flanking region upstream of the structural Q6 gene contain a promoter that functions as a transcription initiation site in L cells. The 3' portion of the Q6 gene appears to be responsible for the lack of cell surface expression of the intact Q6 and the hybrid Ld/Q6 genes in mouse fibroblasts. Accordingly, this portion of the Q6 class I gene may play a regulatory role in tissue-specific expression. Serological analyses of hybrid Q6 proteins suggested that Q6 may be a structural gene for CR (H-2 crossreactive) antigen found normally on subpopulations of lymphocytes. If this identification is correct, Q6 gene will define a new category of class I genes encoding approximately 40,000 mol wt molecules and carrying a characteristic truncated cytoplasmic tail. Analysis of L cells transfected with Q6 hybrid genes demonstrated also that the cytotoxic T cells specific for Qa-2a region-coded antigens recognize the amino-terminal alpha 1-alpha 2 domain of Q6 fusion products. This recognition can be blocked by anti-Qa-2a alloantiserum and monoclonal antibodies reactive with the alpha 3-beta 2-microglobulin portion of the Q6 hybrids. We propose that the structural requirements for the anti-Qa-2a cytotoxic T lymphocyte-specific epitopes on target molecules are the same as for anti-H-2-alloreactive cytotoxic T lymphocyte determinants on transplantation antigens and that the mechanism of target recognition is similar in both cases. This interpretation is consistent with the following structural similarities found in both categories of class I molecules: (a) Kd and Q6 alpha 1-alpha 2 domains share serologically defined epitopes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

Correlation of intrathymic tolerance with intrathymic chimerism in neonatally tolerized mice.

T cell tolerance to alloantigens can be induced in neonatal mice by the injection of semiallogeneic adult spleen cells. The thymus of neonatally injected mice rapidly becomes specifically unresponsive to the alloantigens expressed by the injected cells, even though the level of chimerism in the thymus of such mice is reportedly marginal compared with that of the periphery. In this report, we have studied the immune reactivity and degree of chimerism in the thymuses of 24 neonatally injected mice. In 13 older mice, the proliferative response of the thymocytes from individual mice to the injected alloantigen varied from strong reactivity to complete tolerance. Interestingly, analysis by flow microfluorometry of the same thymocytes for the presence of the inoculated alloantigen revealed an inverse correlation. That is, the thymuses which had a greater degree of chimerism were tolerant and those with fewer or no detectable cells were partially or totally reactive. The thymuses of 11 younger neonatally injected mice were invariably tolerant to both the MHC and Mls alloantigens of the F1 inocula. Analysis by flow microfluorometry of the thymocytes of these mice revealed that significant numbers of F1 cells reside in the thymuses of mice injected as neonates with semiallogeneic cells. These cells represent a possible source of specific tolerogen for thymocytes during their intrathymic differentiation.

Aging↗

PubMed1985

In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2.

Purified recombinant human interleukin 2 (RIL 2) derived from E. coli containing the inserted gene encoding for IL 2 was administered to 20 patients with a variety of malignancies. Toxicity was dose related and included fever, chills, malaise, arthralgias, myalgias, and unexpectedly, weight gain related to marked fluid retention. All patients receiving more than 10(5) U/kg total cumulative dose developed evidence of fluid retention, and all patients requiring discontinuance of RIL 2 (11/20) received total doses of between 2.54 X 10(5) U/kg to 15.4 X 10(5) U/kg. The limiting dose with this preparation was 3000 U/kg/hr by continuous administration or 10(6) U/kg by bolus administration. IL 2 was rapidly cleared from the plasma, with a half life of 6.9 min, and a later delayed clearance was consistent with a two-compartment model, with slower release from the extravascular space back into the plasma compartment. A marked change in lymphoid cells in the periphery was noted with an early depletion of all lymphoid cells, followed by an expansion of such cells with continuous IL 2 administration. A twofold to 16-fold expansion of total lymphoid cells in the peripheral blood could be demonstrated. TAC+ cells representing up to 25% of the circulating peripheral blood mononuclear cells could be demonstrated with 3 wk of continuous RIL 2 administration. Interferon-gamma levels increased in patients treated with IL 2. Precursors of lymphokine-activated killer cells generated under standard conditions were depleted within 2 to 3 min after IL 2 administration, but repopulated the peripheral blood after 7 to 10 days of continuous IL 2 administration. No tumor regression was seen in any of the cancer patients treated with IL 2 alone.

Adrenocorticotropic Hormone↗

PubMed1985

In vivo administration of purified human interleukin 2. I. Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2.

A total of 12 patients with cancer or the acquired immunodeficiency syndrome have been treated with Jurkat-derived purified human interleukin 2 (IL 2). The toxicity was dose-related and consisted primarily of fever, chills, malaise, and mild reversible hepatic dysfunction. No evidence of clinical efficacy was seen when IL 2 was administered at doses of up to 2000 micrograms by bolus or continuous infusion once a week for 4 wk. No significant chronic immunologic effects (changes in mitogen responsiveness of induction of cytotoxic cells) were demonstrated. IL 2 was measured in the serum of patients, and a half-life of approximately 5 to 7 min was demonstrated with a second component of clearance of 30 to 120 min. Heating the serum at 56 degrees C for 30 min allowed for detection of smaller quantities of IL 2 by removing a serum inhibitor whose effect was seen at dilutions of up to 1/80 in our biologic assay. Sustained levels of IL 2 could be maintained by continuous infusion. Acute effects of IL 2 administration included a rapid decrease in peripheral mononuclear cells with a shift to cells of macrophage lineage and a rapid decrease in total T lymphocytes and T lymphocyte subsets. IL 2 responsiveness of peripheral mononuclear cells decreased within 15 min of IL 2 administration, with a concurrent decrease in the ability to generate lymphokine-activated killer cells. These changes did not recover until 48 hr after IL 2 administration. A rise in serum ACTH and cortisol levels was seen after the administration of 1 to 2 mg of IL 2. Future studies will evaluate the role of larger quantities of recombinant IL 2 given alone or in conjunction with in vitro-generated lymphokine-activated killer cells.

Acquired Immunodeficiency Syndrome↗

PubMed1984

In vivo and in vitro characterization of specific hyporeactivity to skin xenografts in mixed xenogeneically reconstituted mice (B10 + F344 rat----B10).

Mixed xenogeneically reconstituted mice (F344 rat + C57BL/10Sn----C57BL/10Sn), which specifically retain F344 tail skin xenografts, were studied for the specificity of such hyporeactivity and for in vitro reactivity and immunocompetence. Survival of mixed reconstituted animals was excellent, without evidence for graft vs. host disease. Donor-type tail skin grafts were specifically prolonged (mean survival time = 80 d) in comparison with normal controls and syngeneically reconstituted animals. In vitro, such animals manifested specific hyporeactivity by mixed lymphocyte reaction and cell-mediated lympholysis to F344 rat and B10 cells, with normal response to third-party rat (Wistar-Furth) and mouse (B10.BR). Examination of lymphoid tissues with a fluorescence-activated cell sorter revealed low levels, if any, of donor-type cells detectable. This system offers a model for investigation of xenogeneic transplantation tolerance.

Animals↗

PubMed1984

Expression of interleukin 2 receptors on activated human B cells.

Using anti-Tac, a monoclonal anti-interleukin 2 (IL-2) receptor antibody, we have explored the possibility that certain activated B cells display receptors for IL-2. Resting normal B cells and unselected B cell lines established from normal individuals were Tac antigen negative. In contrast, the cell surface Tac antigen expression was demonstrable on 6 of 10 B cell lines from patients with Burkitt's lymphoma, 5 of 6 B cell lines derived from patients with HTLV-I-associated adult T cell leukemia (including all four that had integrated HTLV-I into their genome), and on certain normal B cells activated with pokeweed mitogen. Furthermore, cloned Epstein-Barr virus-transformed B cell lines derived from Tac-positive normal B cells continued to express the Tac antigen in long-term cultures and manifested high affinity IL-2 receptors identified in binding studies with purified radiolabeled IL-2. The line 5B4 developed in the present study could be induced with purified JURKAT-derived or recombinant IL-2 to express a larger number of IL-2 receptors. Furthermore, the addition of IL-2 to the 5B4 B cell line augmented IgM synthesis, which could be blocked by the addition of anti-Tac. The size of the IL-2 receptors expressed on the cloned normal B cell lines was similar (53,000-57,000 daltons) to that of receptors on phytohemagglutinin-stimulated T cell lymphoblasts. Thus, certain malignant and activated normal B cells display the Tac antigen and manifest high affinity receptors for IL-2. These data suggest that IL-2 may play a role in the differentiation of activated B cells into immunoglobulin-synthesizing and -secreting cells.

Antibodies, Monoclonal↗

PubMed1984

Serologic cross-reactivity between Class I MHC molecules and an H-2-linked differentiation antigen as detected by monoclonal antibodies.

Analysis of anti-Class I major histocompatibility complex (MHC) monoclonal antibodies by immunofluorescence and flow microfluorometry demonstrated an unexpected cross-reactivity. Two of fifteen antibodies examined (20-8-4, anti-Kb,Kd,r,s and 34-1-2, antiKd,Dd,Kb,r,s,q,p) were observed to detect an antigen determined by gene(s) mapping to the right of H-2D. Two-color immunofluorescence analysis demonstrated that this antigen, unlike classical H-2K and D antigens, was expressed in high amounts on peripheral T cells, but only weakly on Ia-positive cells and on small subpopulations of thymus and bone marrow cells. Mapping, absorption, blocking, and tissue distribution studies suggested that the cross-reactive antigen is Qa-like, but distinct from previously described Qa antigens. Thus, these data demonstrate serological cross-reactivity between a Class I MHC antigen and a differentiation antigen determined by genes linked to H-2. It seems likely that the gene responsible for this new antigen is one of the numerous Class I-like sequences detected by DNA hybridization analyses, but previously undefined in terms of tissue expression. These data suggest that many of these DNA sequences may be expressed in specific tissues and that cross-reactions of anti-Class I MAbs may provide useful probes for studying the products of such homologous genes.

Absorption↗

PubMed1984

Analysis of lymphocyte subsets in patients with aplastic anaemia.

Lymphocyte subsets have been measured in the blood of 28 patients with aplastic anaemia. The mean helper/inducer:suppressor/cytotoxic T lymphocyte ratio (1.24 +/- 0.74) was significantly decreased in the total population in comparison to mean ratios in a normal population (1.78 +/- 0.57) and in patients with other haematological diseases (1.82 +/- 0.92). A reversed ratio (less than or equal to 1) was present in a large proportion (53%) of aplastic patients, due both to an absolute deficiency of helper/inducer lymphocytes and an increase in suppressor/cytotoxic lymphocytes. Increased HLA-DR expression, evidence of lymphocyte activation, was present in seven of 12 patients evaluated and was confined to the suppressor/cytotoxic lymphocyte population. In the bone marrow, the percentage of lymphocytes was increased two-fold compared to normal bone marrow but the ratio of T cell subsets was not abnormal. Two of four patients evaluated after haematopoietic recovery following ATG treatment showed a return to normal of the T4/T8 ratio; in two others a low T4/T8 ratio persisted despite recovery. These results indicate that lymphocyte subset imbalance and lymphocyte activation are present in many patients with aplastic anaemia, either as a contributing factor or as a result of bone marrow failure.

Adolescent↗

PubMed1984

Non-activated guinea-pig T cells and thymocytes express Ia antigens: FACS analysis with alloantibodies and monoclonal antibodies.

Conventional alloantisera and monoclonal antibodies to guinea-pig Ia antigens were used for analysis of Ia expression by guinea-pig T cells and thymocytes. Indirect immunofluorescent staining was performed with alloantisera or with ascitic fluid as a source of monoclonal antibody followed by flow microfluorometry analysis on the fluorescence activated cell sorter. About 80% of normal, non-activated peritoneal exudate T cells, lymph node T cells and thymocytes expressed Ia antigens. These data are therefore in contrast to studies with human or murine T cells where Ia antigens were shown to be expressed predominantly on activated but not on non-activated T cells. All the reactivity of the anti-Ia alloantisera for strain 2 T cells could be removed by absorption with an Ia-bearing B cell leukaemia, EN-L2C, but not by its Ia-negative variant, BZ-L2C. Thus, the Ia determinants identified on T and B cells are probably identical. One monoclonal antibody, 25E3, which had previously been shown by serologic analysis to react exclusively with an alloantigenic determinant of strain 2 Ia antigens displayed an unusual pattern of reactivity in that it clearly stained strain 13 thymocytes, but not mature strain 13 T or B lymphocytes. The significance of this possible expression of inappropriate Ia determinants by thymocytes remains unclear. This phenomenon might be associated with differentiation processes in the thymus.

Animals↗

PubMed1984

Systemic administration of interleukin-2 in humans.

Twelve patients were treated in a Phase I trial of purified human interleukin-2 (IL-2) derived from the JURKAT cell line (E.I. duPont Corp., Glenolden, PA, U.S.A.). The serum half-life, toxicity, and in vivo immunologic effects of IL-2 were studied in patients with cancer unresponsive to standard therapy and in patients with acquired immunodeficiency syndrome (AIDS). Patients received 0.25, 2.5, or 25 micrograms/kg IL-2 by bolus or 24-h continuous infusion on a weekly basis for 4 weeks. The serum half-life of JURKAT IL-2 in humans was approximately 6 min. At higher doses of IL-2 a second component of clearance with a half-life of 30-120 min was found. Acute toxicity was minimal and consisted of headache (6 of 12), nausea (4 of 12), malaise (6 of 12), and fever and chills (8 of 12). No evidence of pulmonary, hematologic, or renal toxicity or any evidence of autoimmune phenomena was detected. A transient hyperbilirubinemia was seen in two patients receiving 2 mg purified IL-2. No demonstrable effect on tumors or chronic immunodeficiency (AIDS) was seen. No consistent chronic immunologic effects (natural killer or lymphokine-activated killer activity, mitogen responsiveness, total lymphocyte counts, or change in the proportion of various mononuclear cell phenotypes as defined by monoclonal antibody) were seen on a week-to-week basis during or following therapy. Acute changes in lymphokine responsiveness, the ability to generate lymphokine-activated killers, and an increase in macrophages in the mononuclear population were noted following administration of 1-2 mg IL-2.

Acquired Immunodeficiency Syndrome↗

PubMed1983

Serologic and functional characterization of a panel of antigen-presenting cell lines expressing mutant I-A class II molecules.

An improved method is described for selecting mutant cells with an altered pattern of Ia antigenic determinants and antigen-presenting properties from an homogeneous population of functional antigen-presenting cells (APC). The APC line used, TA3, was a somatic cell hybrid obtained by fusing normal heterozygous H-2a/d B cells with a drug-marked variant of a BALB/c B lymphoma line. Two phenotypic groups of mutants were obtained by this method. Serologic analysis with a panel of anti-I-Ak monoclonal antibodies suggested that the change in the first group of mutants (type A mutants) involved the alteration of a portion of one epitope of the I-Ak molecule while in the second group of mutants (type B), an alteration of a different Ia epitope group had occurred. Functional studies using a panel of cloned antigen-specific and autoreactive T cell hybridomas demonstrated that the loss of a limited number of I-Ak determinants in the type A mutants correlated with the loss of some but not all I-Ak-encoded restriction elements, while the type B mutation(s) resulted in the ablation of all I-Ak-restricted APC functions tested. These mutations may occur in the region of the Ia molecule that interacts with the T cell receptor (the histope) or in a postulated region that interacts with antigen (the desetope). The finding that both type A and B mutations lead to loss in the capacity to be corecognized with many different antigens by I-Ak-restricted T cell hybridomas suggests that the Ia molecule may possess very few distinct histotopes and/or desetopes or that the tertiary structure of the Ia molecule is crucial in the formation of these sites. Alternatively, the mutations, particularly the type B mutations, may have led to the failure of expression of an entire alpha or beta chain.

Animals↗

PubMed1983

T cell tolerance to non-H-2-encoded stimulatory alloantigens is induced intrathymically but not prethymically.

The present report has evaluated the differentiation compartment in which T cells are tolerized to non-major histocompatibility complex (MHC)-encoded minor lymphocyte-stimulating locus (MLS) alloantigens. It was observed that T cell precursors are not tolerized prethymically to MLS alloantigens but are tolerized intrathymically and postthymically to MLS alloantigens. The failure of prethymic T cells to be tolerized indicates either that T cell precursors are unable to be tolerized to MLS alloantigens or that cells in the prethymic compartment are unable to induce MLS-specific tolerance. In either case, these results demonstrate that the thymus is the initial site in which T cell tolerance to MLS alloantigen is induced. The present results also demonstrate a striking disparity in the reactivity of thymocytes to MHC and MLS alloantigens expressed in the extrathymic host through which their precursors had migrated. In the experimental mice constructed for these studies, intrathymic T cells were tolerant to the MHC alloantigens but were reactive to the MLS alloantigens expressed by the extrathymic host. This observation is consistent with the concept that T cell precursors may be tolerized to MHC alloantigens at an earlier point in their differentiation than they are tolerized to non-MHC-encoded MLS alloantigens.

Alleles↗

PubMed1983

Early development of the T cell repertoire. In vivo treatment of neonatal mice with anti-Ia antibodies interferes with differentiation of I-restricted T cells but not K/D-restricted T cells.

Monoclonal antibodies to I-Ak were injected into neonatal H-2k mice for a period of 3 wk. The spleens of such mice are devoid of Ia-positive cells. Allo- and trinitrophenyl (TNP)-self-specific cytotoxic T lymphocyte (CTL) responses in such anti-I-A-treated mice were almost completely abrogated at the end of the 2-3 wk in vivo treatment period. Development of suppressor cells, carry-over of blocking antibodies, lack of responder accessory cells, or defective CTL function were not responsible for the observed defect. As concanavalin A supernatant could restore the defect, it is more likely that the defect is due to the absence of competent Ia-specific T helper cells. In addition, anti-I-A-treated mice exhibit reduced I-A antigen expression in the thymus and defective Ia-bearing accessory cell function in the spleen. It is postulated that, for development of Ia-specific T cells to occur, precursor T cells need to interact with Ia-encoded products in the thymus, and anti-Ia treatment interferes with this process. Finally, the mechanism of this interference was shown to be due to actual removal or functional inactivation of those I-A-positive elements responsible for the education of I-A-recognizing T cells, since in (H-2b X H-2k)F1 mice, treatment with anti-I-Ak antibodies results in abrogation of CTL responses to TNP in association with both parental haplotypes, while in the thymus of these mice expression of both I-Ak and I-Ab was reduced.

Animals↗