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Biomedical subjects

H J Winn

Publications and source records attributed to H J Winn.

At least 19 recordsLinked to original sources
PubMed1992

Evidence that multiple defects in cell-surface molecule interactions across species differences are responsible for diminished xenogeneic T cell responses.

The purpose of the present study was to identify which of the several possible defects in cell-surface-molecule interactions are responsible for diminished mouse helper T cell responses to xenoantigens. We measured primary mouse anti-monkey, anti-pig, and anti-human proliferation in vitro in experimental systems in which potential defects were partially corrected by lymphokine supplementation and/or the use of transgenic or hybridoma cell populations. We found that the diminished mouse helper T cell responses to xenoantigens result from at least two defects in cell-surface-molecule interactions between T cells and xenogeneic APCs, specifically TCR and/or CD8 interactions with xenogeneic class I MHC molecules and accessory molecule interactions with their ligands (probably LFA-1 with ICAM-1/ICAM-2 and/or LFA-2 with LFA-3). Other investigators have identified additional defects, such as in lymphokine function across species differences. Thus, there appear to be multiple defects responsible for the diminished cellular immune response to xenoantigens.

Animals↗
PubMed1992

Transplantation effects of a unique major histocompatibility complex class I mutation.

This study describes a novel MHC class I mouse mutant that was discovered because of loss of reactivity of its cells to monoclonal antibodies. The mutation occurred in the H-2Ks molecule and is the first in vivo mutation described that has a single altered amino acid residue (amino acid 107) distant from the regions considered to be peptide or TCR contacts. Nevertheless, skin grafts from the mutant to the parent are rejected by CD8+ T-cells. In the reciprocal direction, the mutant shows partial tolerance to parental skin grafts, suggesting that the mutant is inefficient in selecting alloreactive T-cells specific for the wild-type Ks molecule.

Animals↗
PubMed1991

Studies on murine natural killer (NK) cells. V. Genetic analysis of NK cell markers.

This paper attempts to clarify the number and nomenclature of murine natural killer (NK) cell specific alloantigens by defining the genetic relationships between them, that is, are they coded by loci which are independent, allelic, or linked. Strain typing and F2 analyses using five alloantisera (C3H X BALB/c)F1 anti-CE, CE anti-CBA, NZB anti-BALB/c, C3H anti-ST, and BALB/c anti-DBA/2 revealed that (a) the alloantigens NK-1.1 and NK-3.1 are determined by distinct loci which are linked on the same chromosomes, (b) the alloantigen NK-2.1 is determined by an independently segregating locus to those coding for NK-1.1 and NK-3.1, (c) the alloantisera, CE anti-CBA and NZB anti-BALB/c, which have been designated anti-NK-2.1 alloantisera recognize different alloantigens coded by independent genetic loci. Thus, these five alloantisera detect four NK cell specific alloantigens which, based on the chronology of their discovery, have been designated NK-1.1-(C3H X BALB/c)F1 anti-CE, NK-2.1-CE anti-CBA, NK-3.1-C3H anti-ST, and BALB/c anti-DBA/2 and NK-4.1-NZB anti-BALB/c.

Animals↗
PubMed1990

Xenogeneic proliferation and lymphokine production are dependent on CD4+ helper T cells and self antigen-presenting cells in the mouse.

We studied proliferation and interleukin 2 production by B6 mouse spleen cells in response to stimulation by irradiated cynomolgus monkey spleen cells and compared the results with responses against whole MHC-disparate allogeneic controls (BALB/c). We found that (a) primary xenogeneic helper responses were absent, whereas primary allogeneic responses were brisk, (b) secondary xenogeneic helper responses were dependent on CD4+ T cells and responder antigen-presenting cells (APCs), whereas allogeneic responses could be mediated by either CD4+ or CD8+ T cells independently and were primarily dependent on the presence of stimulator APCs, and (c) secondary xenogeneic helper responses were blocked by an antibody directed against responder class II MHC molecules. These results suggest that mouse helper T cells recognize disparate xenoantigens as processed peptides in association with self class II MHC molecules, similar to the recognition of nominal antigens and unlike direct allo-recognition.

Animals↗
PubMed1990

Xenograft rejection of class I-expressing transgenic skin is CD4-dependent and CD8-independent.

B10.PD1 mice are transgenic animals expressing a class I MHC antigen of pigs. B10.PD1 skin graft survival on B6 mice was prolonged by anti-CD4 antibody treatment in vivo but not by anti-CD8 treatment. These results suggest: (1) that the defect in cell-mediated recognition of xenografts involves an interaction with the xeno-MHC antigens themselves and not with the cells which express them; (2) that antigen processing and presentation of xeno-antigens on responder-type APCs is required in vivo; and (3) that CD8-independent, possibly noncytotoxic, mechanisms of xenograft rejection may exist.

Animals↗
PubMed1989

Murine CD8+ T cell helper function is particularly sensitive to cyclosporine suppression in vivo.

In order to investigate the mechanism of action of cyclosporine (CsA) in vivo the drug was used to prolong the survival of different types of allogeneic skin grafts on mice under different conditions. Lower doses of CsA were necessary to prolong class I-disparate grafts than to prolong class II-disparate grafts than to prolong whole MHC-disparate grafts. Second set skin grafts, even of class I-only disparity, could not be prolonged even by higher doses of CsA. Primary class I-disparate grafts, which survived at a low dose of CsA, were rejected at the same dose if a second inducer graft was also placed expressing the same class I Ag plus other mismatched class II Ag. A suboptimal dose of CsA was synergistic with an anti-CD4 mAb but not with an anti-CD8 antibody for whole MHC-mismatched grafts. These results support the notion that CsA interferes with helper T cell function in vivo and suggest that CD8+ helper function is particularly sensitive to CsA suppression.

Animals↗
PubMed1989

Xenogeneic skin graft rejection is especially dependent on CD4+ T cells.

B6 mice were treated in vivo with anti-CD4, anti-CD8, or both anti-T cell antibodies together in an effort to prolong xenogeneic compared with allogeneic skin graft survival. Mice treated with anti-CD4 antibody showed prolonged survival of xenogeneic monkey or rabbit skin even after they had rejected whole MHC-disparate allogeneic mouse skin. Furthermore, the addition of cyclosporine was synergistic with the anti-CD4 antibody in prolonging graft survival. These results suggest that the cell-mediated response to xenogeneic antigens is especially dependent on CD4+ lymphocytes, a feature shared by the response to allogeneic minor histocompatibility antigens. In addition, the results suggest a possible approach to clinical immunosuppression for some forms of xenogeneic transplantation.

Animals↗
PubMed1989

In vivo use of monoclonal antibodies against murine T cell antigens.

Experiments were performed seeking conditions for the optimum use of anti-T cell monoclonal antibodies in vivo in mice. Anti-L3T4 (CD4) and anti-Lyt2 (CD8) antibodies of different subclasses (IgG2b, IgG2a, and IgM) and species (rat or mouse) were used. The results showed that (i) intraperitoneal compared to intravenous administration of the different antibodies achieved the same serum levels whether in the presence or absence of the recipient's thymus; (ii) repeated treatment with a rat IgM anti-L3T4 or a rat IgG2b anti-Lyt2 antibody was followed by inability to detect serum levels of each antibody; (iii) in vivo treatment with these antibodies caused target cell lysis, target antigen masking without cell destruction, or target antigen modulation without cell destruction and the particular effect of a given antibody could not be predicted by its isotype or specificity; (iv) neither the C5 component of complement nor antibody-dependent cell-mediated cytotoxicity mediated the action of GK1.5 antibody in vivo; (v) dose-response curves of in vivo potency of a given antibody could not be predicted by in vitro assays; (vi) thymocytes were depleted by monoclonal antibody treatment by using 1000-fold more antibody than needed to deplete peripheral lymphocytes; (vii) the rate of return of target T cells after depletion in nonthymectomized mice depended on the dose of the antibody; and (viii) thymectomy prolonged the effect of most, but not all antibodies. In thymectomized mice, CD8+ cells remained almost undetectable for prolonged periods of time after depletion while CD4+ cells returned to approximately 30% of their original level and remained constant over time after initial complete depletion. These results provide useful data for the effective use of monoclonal anti-T cell antibodies in mice. They stress the difficulty of predicting the in vivo effects of monoclonal antibodies without actually testing them in vivo. They include new insights into mechanisms of action of monoclonal antibodies and the role of thymectomy in prolonging their effect. They describe the unrecognized ability of antibodies to deplete thymocytes.

Animals↗
PubMed1989

Studies on natural killer (NK) cells IV NK-3.1: a new NK cell specific alloantigen.

A new murine natural killer (NK) cell alloantigen, NK-3.1, has been identified by analysis of the complement dependent anti-NK cell activity of C3H anti-ST and BALB/c anti-DBA/2 alloantisera. Flow cytometric studies with a specific antiserum made in backcross mice indicate that this alloantigen is expressed by 2-3% of the spleen cells of NZB and C57BL/6 mice, positive strains, but is undetectable on the spleen cells of C3H mice, a negative strain. Since NK-1.1 and NK-2.1 are also expressed on 2-3% of spleen cells of positive strains we suggest that all three alloantigens identify the NK cells in normal mouse spleen which lyse the lymphoma target cell line YAC.

Absorption↗
PubMed1988

Prevention of alloantibody formation after skin grafting without prolongation of graft survival by anti-L3T4 in vivo.

Treatment of mice in vivo with monoclonal antibodies against the L3T4 antigen (CD4 in human beings) has been shown to suppress the humoral response to several foreign antigens and to prolong the survival of allografts in some cases. Experiments were therefore performed to test whether anti-L3T4 antibody treatment would suppress alloantibody production after skin transplantation. Monoclonal anti-L3T4 antibody (GK1.5) was administered to C57BL/6 (B6) mice prior to BALB/c skin grafting. The production of B6 anti-BALB/c alloantibody was then tested after graft rejection. The results showed that: (1) graft survival of BALB/c skin on B6 mice was not substantially prolonged by anti-L3T4 treatment; (2) graft survival was significantly prolonged if mice were treated with both anti-L3T4 and anti-Lyt2 antibody; (3) the production of alloantibody following grafting was decreased by anti-L3T4 treatment and was completely eliminated if thymectomy was also performed; (4) thymectomy prolonged the effectiveness of the anti-L3T4 treatment; (5) tolerance to alloantigens presented at the time of anti-L3T4 treatment was not achieved; and (6) well-established cytotoxic antibody titers rose to higher levels after secondary grafting even with concurrent anti-L3T4 treatment, while weak antibody titers remained stable or decreased. These results indicate that L3T4+ cells are essential in providing the "help" necessary for generating humoral responses to alloantigens but that elimination of these L3T4+ cells still allows the generation of help for cell-mediated immunity. The data also suggest that class I antigens must be presented on class II molecules in order to elicit an antibody response.

Animals↗
PubMed1988

Immunohistochemical analyses of skin graft rejection in mice. Kinetics of lymphocyte infiltration in grafts of limited immunogenetic disparity.

We have examined the nature and kinetics of T cell infiltration into murine first-set skin allografts across a variety of histocompatibility differences. Both Ly 1+2- and Ly 2+ cells migrate into grafts that differ with respect to discrete class I, class II, or minor H barriers. The lymphoid cells in the allograft did not express MEL 14 or the B cell antigen B220. The cells in the graft progress from the vascular anastomosis region into the dermis with apparent homing and clustering about hair follicles and epithelial cells at the dermoepidermal junction. Microscopic necroses appear in a patchy distribution in these areas. The intensity of the infiltrate is related to the nature of the alloantigen recognized but it does not correlate with the tempo of rejection. Class II-disparate allografts evoke a peak response (mean 62 +/- 34 T cells/0.1 mm2) that is 2-6-fold greater than class I-disparate allografts or syngeneic control peak responses (mean 14 +/- 2.4 T cells/0.1 mm2). Although a difference at a minor H antigen evoked an intense peak T cell response (192 +/- 33 T cells/0.1 mm2), the mean survival time of the allografts was significantly longer than that observed with class I or class II differences. The IL-2 receptor+ subset of activated T cells is extremely rare in syngeneic grafts, but ranges from 0 to 56% of infiltrating T cells in allografts. We conclude that all major T cell subsets contribute to the in situ response to all classes of alloantigens, but at the apparent exclusion of the MEL 14+ T cell pool and B cells.

Animals↗
PubMed1986

Monoclonal antibody therapy. Anti-idiotypic and non-anti-idiotypic antibodies to OKT3 arising despite intense immunosuppression.

The frequency, timing, and specificity of the humoral antibody response to a murine monoclonal antibody (OKT3, IgG2a) were measured in 21 consecutive renal allograft recipients. These patients received i.v. OKT3, 1-5 mg/day for 10-20 days as treatment for acute graft rejection. Maintenance immunosuppression consisted of azathioprine and corticosteroids. Using three different assays, an antibody response was detected in 75% of the 20 patients with adequate samples. The ELISA assay of the overall IgM and IgG reactivity to OKT3 revealed that IgM anti-OKT3 appeared in 65% and IgG anti-OKT3 in 50% of the patients, reaching a peak 20-33 days after the last dose of OKT3. The IgM preceeded the IgG in most cases (P less than 0.02) and in 8 cases was detected during therapy. One patient had high levels of IgM anti-OKT3 before therapy, yet responded normally to OKT3. Interference with the therapeutic effectiveness was evident in one patient who developed IgG antibodies during therapy. His serum blocked the binding of F-OKT3 to normal lymphocytes in the presence of normal BALB/c serum. The blocking assay, done by flow cytometry, measured anti-idiotypic (Id) reactivity since the sera did not affect the binding of OKT8 (another IgG2a) or anti-Leu4 (another anti-T3), and the blocking activity remained after affinity absorption with normal mouse IgG. Using this assay, 60% of the patients made an anti-Id response. One made only anti-Id, and several had anti-Id at times when other reactivities were undetectable. Antibodies to non-idiotypic, presumably isotypic, determinants represented on OKT8 occurred in only 44%, while other reactivity (OKT4; IgG2bK) was less common (12%) and weaker. While no adverse allergic reactions occurred in this group of patients, the anti-Id antibodies, which are a prominent feature of the immune response to this and probably other monoclonal antibodies, can block their therapeutic effectiveness and can arise despite intense immunosuppression. This response may require the use of different idiotypes for prolonged or repeated courses of therapy and may be the major obstacle to the use of human monoclonal antibodies.

Antibodies, Anti-Idiotypic↗