Alternative pathways of T lymphocyte activation.
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Data presented in this paper suggest that there may be two alternative pathways which T lymphocytes can use in generating a cytotoxic response to alloantigens in vitro. First, there is the pathway taken when stimulator and responder cells differ by an entire H-2 complex where Ly1+2- helper T lymphocytes respond to I region encoded lymphocyte defined differences and provide help to the Ly1-2+ cytotoxic T lymphocytes responsive primarily to K/D region encoded cytotoxicity defined determinants. Second, there is the pathway taken when stimulator and responder cells differ by only K or D region differences without an I region encoded difference; under these conditions, an Ly1+2+ cell, which does not appear to play a significant role in the development of a cytotoxic response to an entire H-2 difference, appears to play a pivotal role. (+info)
Human antibody responses to mature and immature forms of viral envelope in respiratory syncytial virus infection: significance for subunit vaccines.
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A number of antibodies generated during human respiratory syncytial virus (RSV) infection have been cloned by the phage library approach. Antibodies reactive with an immunodominant epitope on the F glycoprotein of this virus have a high affinity for affinity-purified F antigen. These antibodies, however, have a much lower affinity for mature F glycoprotein on the surface of infected cells and are nonneutralizing. In contrast, a potent neutralizing antibody has a high affinity for mature F protein but a much lower affinity for purified F protein or F protein in viral lysates. The data indicate that at least two F protein immunogens are produced during natural RSV infection: immature F, found in viral lysates, and mature F, found on infected cells or virions. Binding studies with polyclonal human immunoglobulin G suggest that the antibody responses to the two immunogens are of similar magnitudes. Competitive binding studies suggest that overlap between the responses is relatively limited. A mature envelope with an antigenic configuration different from that of the immature envelope has an evolutionary advantage in that the infecting virus is less subject to neutralization by the humoral response to the immature envelope that inevitably arises following lysis of infected cells. Subunit vaccines may be at a disadvantage because they most often resemble immature envelope molecules and ignore this aspect of viral evasion. (+info)
Inhibition of allorecognition by a human class II MHC-derived peptide through the induction of apoptosis.
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The interaction of the T-cell receptor with the major histocomatibility complex (MHC)-peptide complex is central to T-cell activation. Variation in the nature of the peptide bound within the groove of the MHC molecule may result in an altered T-cell response. Because some naturally processed peptides bound within the groove of the class II MHC molecule are derived from the MHC molecules themselves, we studied the inhibitory effects of synthetic class II MHC peptides on alloimmune responses in vitro. Three peptides derived from a highly conserved region of the class II MHC alpha chains inhibited the rat mixed lymphocyte response (MLR) in a dose-dependent manner, with the human HLA-DQA1 peptide also inhibiting the human and mouse MLR. No effect was seen on mitogen-induced T-cell proliferation. HLA-DQA1 inhibited cytolytic T lymphocyte (CTL) generation in a dose-response fashion, with no reduction in preformed CTL killing, suggesting that the inhibitory effect is targeted at CD4(+) T-cell function. Cell-cycle analysis by flow cytometry showed that restimulation of primed T cells in the presence of HLA-DQA1 resulted in increased apoptosis, whereas unstimulated cells were not affected. These data demonstrate that synthetic peptides derived from highly conserved regions of the class II MHC alpha chain can alter CD4(+) T-lymphocyte alloimmune responses in vitro, and this effect is mediated by the induction of apoptosis in activated T cells. (+info)
Antifactor VIII antibody inhibiting allogeneic but not autologous factor VIII in patients with mild hemophilia A.
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Two unrelated patients with the same Arg2150His mutation in the factor VIII (FVIII) C1 domain, a residual FVIII activity of 0.09 IU/mL, and inhibitor titres of 300 and 6 Bethesda Units, respectively, were studied. Further analysis of patient LE, with the highest inhibitor titer, showed that (1) plasma or polyclonal IgG antibodies prepared from LE plasma inhibited the activity of allogeneic (wild-type) but not of self FVIII; (2) the presence of von Willebrand factor (vWF) increased by over 10-fold the inhibitory activity on wild-type FVIII; (3) the kinetics of FVIII inhibition followed a type II pattern, but in contrast to previously described type II inhibitors, LE IgG was potentiated by the presence of vWF instead of being in competition with it; (4) polyclonal LE IgG recognized the FVIII light chain in enzyme-linked immunosorbent assay and the recombinant A3-C1 domains in an immunoprecipitation assay, indicating that at least part of LE antibodies reacted with the FVIII domain encompassing the mutation site; and (5) LE IgG inhibited FVIII activity by decreasing the rate of FVIIIa release from vWF, but LE IgG recognized an epitope distinct from ESH8, a murine monoclonal antibody exhibiting the same property. We conclude that the present inhibitors are unique in that they clearly distinguish wild-type from self, mutated FVIII. The inhibition of wild-type FVIII by LE antibody is enhanced by vWF and is associated with an antibody-dependent reduced rate of FVIIIa release from vWF. (+info)
Isolation and characterization of monoclonal antibodies directed against murine FRP-1/CD98/4F2 heavy chain: murine FRP-1 is an alloantigen and amino acid change at 129 (P<-->R) is related to the alloantigenicity.
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Nineteen mAb directed against murine fusion regulatory protein-1 (mFRP-1)/4F2/CD98 were isolated and their biological properties were analysed. Intriguingly, mFRP-1 was found to be an alloantigen, namely, FRP-1.1 (DBA/2 and CBA mice type) and FRP-1.2 (BALB/c, C57BL/6 and C3H/He mice type). The nucleotide sequences of FRP-1.1 and FRP-1.2 were determined, demonstrating that amino acid change at 129 (P<-->R) is related to the alloantigenicity. mFRP-1 is expressed on thymocytes, on spleen cells, on peripheral lymphocytes and on blood monocytes, suggesting that the physiological role in vivo of murine FRP-1 is different from that of human FRP-1. The biological activities of antimFRP-1 mAbs showed by the present study are: (i) enhancement of Newcastle disease virus-induced cell fusion; (ii) suppression of HIVgp160-mediated cell fusion; and (iii) induction of aggregation and multinucleated giant cells of monocytes/macrophages. (+info)
Administration of G-CSF to normal individuals diminishes L-selectin+ T cells in the peripheral blood that respond better to alloantigen stimulation than L-selectin- T cells.
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To determine whether administration of G-CSF induces phenotypic or functional changes in T cells, we examined peripheral blood T cells from normal individuals receiving G-CSF for activation antigen and adhesion molecule expression before and after G-CSF administration. G-CSF (10 microg/kg/day) was administered subcutaneously to 14 normal individuals for 3-5 days and their PBMC were serially analyzed with monoclonal Ab (mAb) directed to HLA-DR, CD45RO, CD45RA, CD25, CD122, CD95, CD11a, CD49d, CD44 and CD62L (L-selectin) coupled with anti-CD3 mAb. Among T cells positive for these antigens, only the proportion of T cells expressing L-selectin significantly decreased from 68% to 37% after 3-day G-CSF administration. When peripheral blood CD3+ T cells obtained before and after G-CSF administration were sorted into two populations depending on the expression of L-selectin and tested for their proliferative response to allogeneic B cells, the reactivity of L-selectin- cells to alloantigen stimulation was consistently lower than that of L-selectin+ cells regardless of the exposure to G-CSF. The decrease in the relative number of L-selectin+ cells induced by G-CSF administration may contribute to the unexpectedly low incidence of severe acute GVHD after allogeneic PBSC transplantation. (+info)
Cutting edge: sustained expansion of CD8+ T cells requires CD154 expression by Th cells in acute graft versus host disease.
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Brief treatment with alphaCD154 Ab has been shown to prevent acute graft versus host disease (aGvHD). We extend these data to show that in the absence of CD154 function, donor T cells are unable to expand or generate high level anti-host CTL activity. Using transgenic (Tg) alloreactive CD8+ T cells adoptively transferred into allogeneic recipients, we show that short-term expansion of the CD8+ Tg T cells occurred in the absence of Th cells, and this short-term expansion could be facilitated with an agonistic alphaCD40. While CD40 agonism could enhance short-term expansion, sustained expansion of CD8+ Tg T cells required bona fide CD154-expressing CD4+ alloreactive Th cells. While CD154 was necessary for CD8+ Tg T cell sustained expansion, IL-2 was also implicated as essential. These observations suggest alphaCD154 therapy in GvHD is effective because the treatment causes an abortive CD8 alloresponse leading to the exhaustion or deletion of alloreactive CD8+ clones preventing the development of disease. (+info)
T cell immunity induced by allogeneic microglia in relation to neuronal retina transplantation.
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Microglia share a lineage relationship with bone marrow-derived monocytes/macrophages and dendritic cells, and their inclusion in retinal and brain transplants may function as "passenger leukocytes. " In other solid allografts, passenger leukocytes are the primary sources of immunogenicity, triggering alloimmune rejection. We have conducted a series of in vitro and in vivo studies examining the capacity of microglia cultured from forebrain to activate alloreactive T cells and to induce and elicit alloimmunity. Cultured microglia expressed class II MHC molecules and costimulatory molecules (B7-1, B7-2, and CD40), and they secreted IL-12. Cultured microglia injected s.c. into naive recipients induced allospecific delayed hypersensitivity and elicited delayed hypersensitivity directed at alloantigens. Cultured microglia differed from conventional APCs by secreting significant amounts of mature TGF-beta2, but smaller amounts of IL-12. Moreover, while both cultured microglia and conventional APC stimulated T cell proliferation in vitro, microglia directed the responding T cells toward the Th2 pathway in which IL-4, but not IL-2 and IFN-gamma, was secreted. The abilities of microglia to secrete TGF-beta2, to stimulate alloreactive Th2 cells, and to induce anterior chamber associated immune deviation when injected into the eye of naive allogeneic mice suggest that they are not typical passenger leukocytes. The unique functional properties of cultured microglia may account for the capacity of neonatal retinal tissue transplanted into the eye to alter the systemic alloimmune response in a manner that delays, but does not prevent, graft rejection. (+info)