Transplantation tolerance correlates with high levels of T- and B-lymphocyte activity (original) (raw)
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Bulletin of Experimental Biology and Medicine, 1986
Transplantation of foreign organs and tissues induces a complex chain of reactions in the recipient, which lead ultimately to rejection of the graft. Until recently the main role in graft rejection has been ascribed to cytotoxic lymphocytes (CTL) . Now, however, this view has been questioned . It has been shown by adoptive cell transfer [ii] that a subpopulation of T lymphocytes, enriched with cells with the Lyt l+,2-phenotype (in which, consequently, precursors of CTL were absent), restored transplantation immunity just as effectively in "B mice" as did unfractionated T cells. Several other investigations also indicated that cells not belonging to the CTL population, but possibly effectors of delayed-type hypersensitivity (DTH), participate in rejection of allografts
European Journal of Immunology, 1993
We have reported that, in A/J (A) (H-2a) mice, a partial tolerance to C57BL/10ScSn (B10) (H-2b) skin allografts and a high incidence of lethal lymphoproliferative disorders (LPD) can be induced by the neonatal i.v. injection of 2 × 107 semiallogeneic (B10 × A)F1 spleen cells (SC) (Végh, P., Baranyi, L. and Jánossy, T., Cell. Immunol. 1990. 129: 56). In this study, we show that the incidence and mortality of LPD were continuously growing from 1 month of age until the end of the experiment at 1 year (64% and 36%, respectively). Based on histology, 27% of the diseased mice suffered from lymphoid malignancies. In the remaining cases (73%), reactive histopathological changes were seen in the spleen, lymph nodes (LN), liver and kidneys. The proportion of CD4+Tcells in the spleen and LN as well as that of splenic B cells decreased, while the percentages of mature and immature myeloid cells doubled. The total cell number of each (sub)population, however, was elevated in both lymphoid organs. The cells taking part in the lymphoproliferation were of host (A) and not of donor (F1) origin. Preceding the development of apparent LPD, the SC, LN cell and thymus cell suspensions of 1-month-old tolerized mice showed reduced in vitro proliferative responses to cell and T cell-dependent B cell mitogens (Con A or PWM), while their reactivity to aT cell-independent B cell mitogen (lipopolysaccharide) was essentially unimpaired. This hyporeactivity seems to be functional, because neither histology nor immunophenotyping by flow cytometry revealed significant alterations in the spleen and thymus of such animals, apart from a slight reduction in the ratio of CD4+/CD8+ T cell subpopulations in the spleen. The in vivo T cell-mediated immune response of the tolerized mice was practically normal to third party CBA/Ca (H-2k) allografts. Antithymocyte autoantibodies (ATA) were detected in the sera of 76% of the tolerized mice at 1 month of age (i.e., even before the mass appearence of LPD). ATA as well as antinuclear Ab were present in 65% of the adult tolerized mice, independently of the presence of LPD. Taken together, in A mice neonatally injected with (B10 × A)F1SC, a partial, specific allograft tolerance and a chronic host-vs.-graft disease-like syndrome developed. The latter is manifested in hyporeactivity to T cell mitogens, development of autoantibodies and, subsequently, in progressive LPD and lymphoid malignancies.
Cell-Mediated Immunity and Blocking Serum Activity to Tolerated Allografts in Rats
Journal of Experimental Medicine, 1973
W/Fu rats were neonatally inoculated with bone marrow cells from B/N rats and vice versa. Of the inoculated rats, some were capable of accepting a foreign (B/N or W/Fu) skin graft over the period of observation (i.e. for more than 100 days), while other rats rejected their skin grafts as early as control animals (within 8–12 days) or after a prolonged period of acceptance (20–96 days). Using a microcytotoxicity test, it could be shown that both those rats that rapidly rejected skin grafts and those that kept their grafts during the observation period had lymphocytes capable of destroying cultivated allogeneic cells from the respective strains with whose cells the rats had been inoculated as newborns. The degree of lymphocyte reactivity decreased upon time, so that 4 of 13 rats that had carried "tolerated" skin grafts over more than 84 days had lymphocytes which were nonreactive in the highest dose tested, and the degree of reactivity in the other 9 rats was less than seen ...
Persistence of anti-donor allohelper T cells after neonatal induction of allotolerance in mice
European Journal of Immunology, 1990
Persistence of anti-donor allohelper T cells after neonatal induction of allotolerance in mice* BALB/c mice rendered tolerant to A/J alloantigens by neonatal injection of lox (A/J x BALB/c)F1 spleen cells develop an autoimmune disease associated with a polyclonal activation of donor B cells. To study the mechanisms leading to donor B cell activation in tolerant mice, we prepared mixed lymphocyte cultures (MLC) between splenic T cells from neonatally injected mice and donor-type (A/J X BALB/c)F, or third-party (C57BL/6 x BALB/c)Fl B cells. Tcells from tolerized mice were unable to generate cytotoxicT lymphocytes, to proliferate or to secrete interleukin (IL)2 after stimulation with donor alloantigens in MLC. These T cell responses were present after MLC with third-party antigens, but were of lower intensity than those generated by control BALB/cTcells. In contrast,Tcells from tolerized mice stimulated immunoglobulin production by donor-type (A/J x BALB/c)Fl B cells much more powerfully thanTcells from control BALB/c mice. The stimulation of donor-type (A/J x BALB/c)Fl B cells was polyclonal, as attested by the levels of anti-hapten and anti-DNA antibodies in the MLC supernatants. IgM was the dominant isotype secreted in vitro, but IgGl and IgG3 were also produced in significant amounts. Lysis experiments indicated that theT cells responsible for F1 B cell stimulation in MLC were CD4+ host TcelkTheseT helper cells were alloreactive since they did not stimulate syngeneic BALB/c B cells, and their effect on donor B cells was specifically blocked by anti-donor Ia monoclonal antibodies. Addition of anti-IL 4 monoclonal antibody to MLC between T cells from tolerant mice and (A/J x BALB/c)Fl B cells almost completely abolished the production of IgG1, but not that of IgM or IgG3. Taken together, these findings indicate that neonatal injection of alloantigens in BALB/c mice induces a state of dissociated tolerance, with unresponsiveness of anti-donor T cells secreting IL 2 on the one hand, and persistence of T cells responsible for B cell help and IL 4 secretion on the other hand.
Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues
Journal of immunology (Baltimore, Md. : 1950), 2015
In this study, we showed that aly/aly mice, which are devoid of lymph nodes and Peyer's patches, acutely rejected fully allogeneic skin and heart grafts. They mounted potent inflammatory direct alloresponses but failed to develop indirect alloreactivity after transplantation. Remarkably, skin allografts also were rejected acutely by splenectomized aly/aly (aly/aly-spl(-)) mice devoid of all secondary lymphoid organs. In these recipients, the rejection was mediated by alloreactive CD8(+) T cells presumably primed in the bone marrow. In contrast, cardiac transplants were not rejected by aly/aly-spl(-) mice. Actually, aly/aly-spl(-) mice that spontaneously accepted a heart allotransplant and displayed donor-specific tolerance also accepted skin grafts from the same, but not a third-party, donor via a mechanism involving CD4(+) regulatory T cells producing IL-10 cytokine. Therefore, direct priming of alloreactive T cells, as well as rejection and regulatory tolerance of allogeneic t...
Journal of Experimental Medicine, 1977
The ease of tolerance induction in B lymphocytes from fetal, neonatal, and adult mice was studied in vivo, in a cell transfer system, and in vitro. Three different tolerogens were used: ultracentrifuged BGG, DNP(6)-D-GL, and ultracentrifuged DNP(22)-BGG. Irradiated thymectomized mice were reconstituted with B cells from fetal or neonatal liver or adult spleen or bone marrow. The mice were injected with tolerogen 1 day later. They were given normal thymus cells and challenged with either BGG or DNP(44)-BGG between 4 and 14 days after tolerance induction. With BGG no difference in ease of B-cell tolerance induction was observed in mice reconstituted with B cells from 17-day fetal liver, neonatal liver, 8- day-old spleen, adult spleen, or adult bone marrow. B cells from 14-day fetal donors are relatively resistant to tolerance induction. In contrast, with DNP(6)-D-GL and DNP(22)-BGG B cells from neonatal donors were clearly more susceptible to tolerance induction than were B cells from...
Proceedings of the National Academy of Sciences, 1973
Serum factors present in rats rendered operationally tolerant to skin allografts by inoculation of allogeneic bone-marrow cells as newborns inhibit or “block” the cytotoxic effect of immune lymphocytes in vitro . These blocking factors were specifically removed from tolerant serum by absorption with allogeneic cells and later eluted from the absorbing cells in glycine buffer (pH 3.1). Blocking activity of the eluted material was resolved into fractions of low and higher molecular weight, which may be soluble histocompatibility antigen and specific alloantibody, respectively. Both antigen and antigen-antibody complexes may block in vitro , depending upon the assay used.
Neonatal transplantation tolerance was induced in Bl0.A mice by the injection ofspleen and bone marrow cells from semiallogeneic [C57BL/10(Bl0) X Bl0.A] F1 donors. The neonatally treated mice accepted skin grafts from Bl0 donors. Spleen cells from tolerant animals did not respond by proliferation to tolerated Bl0 antigens in vitro. However, spleen cells from tolerant mice recognized specifrc (Bl0) antigens and synthesized mRNA for the inducible 55-kDa interleukin-2 receptor (IL-2R) as did cells from normal animals. Maintenance of this early phase of cell activation upon contact with tolerated antigens is direct evidence against clonal deletion as a mechanism, in this particular model of neonatally induced transplantation tolerance. o rsgz Acadcmic PK. Inc.