Cellular Mechanisms of Immunologic Tolerance

Nossal, G. J. V.

doi:10.1146/annurev.iy.01.040183.000341

Cited by 493 publications

(231 citation statements)

References 56 publications

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“…The results described here will be discussed in the context of pretransplant transfusion effects (20)(21)(22)(23)(24)(25)(26)(27)(28), the veto cell phenomenon first described by Miller and associates (29)(30)(31)(32)(33)(34)(35)(36), and the concept of peripheral tolerance as opposed to tolerance induced by intrathymic clonal deletion ofantigen-reactive T lymphocytes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) to active suppression, but due to clonal paralysis of antigenreactive Lyt-2+ CTIrp-and 11,2-producing Lyt-2+ T cells . Since donor lymphocytes exhibit clonal anergy to recipient class I MHC antigens, yet express in vitro remarkably efficient veto functions, we believe that the reciprocal peripheral tolerance in the adult chimeric mice is caused, and maintained, by veto activity of donor and recipient cells.…”

Section: Discussionmentioning

confidence: 92%

Induction of peripheral tolerance to class I major histocompatibility complex (MHC) alloantigens in adult mice: transfused class I MHC-incompatible splenocytes veto clonal responses of antigen-reactive Lyt-2+ T cells.

Heeg

Wagner

1990

The Journal of Experimental Medicine

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SummaryThe efficacy and the mode ofaction of pretransplant transfusion with class I major histocompatibility complex (MHC)-disparate splenocytes in establishing a state of peripheral tolerance in adult mice is analyzed. Adult mice injected intravenously with a critical number of N5 x 10' allogenic splenocytes accept skin grafts and develop chimerism in the peripheral lymphatic tissues, but not in thymus and bone marrow. In parallel, a split tolerance evolves : the frequency of class I MHC-reactive Lyt-2+ cytotoxic T lymphocyte precursor (CTIrp)-and interleukin 2 (IIr2)-producing T cells falls off in the peripheral lymphoid tissue, but remains unaltered intrathymically. In particular, high affinity CTLp become clonally undetectable . In vivo generation of tolerant cells is cyclosporin A resistant, but dependent on recipient L3T4+ T cells. Loss of Lyt-2+ CTIrpand IL-2-producing T cell precursors is not due to active suppression, but is caused by clonal anergy. Donor-derived chimeric cells positively selected 7 d after intravenous transfusion exhibit in vitro the hallmarks of veto cells, i.e., paralyze CTLp reactive to donor-type class I MHC alloantigens . We conclude that the peripheral (split) tolerance induced in vivo by pretransplant transfusion operates because donor-type cells develop in vivo efficiently into "veto cells;' which in turn induce a state of clonal anergy within antigen-reactive Lyt-2+ T lymphocytes.A prime aim in transplantation immunology is to define gentle methods able to convert immune reactivity to transplantation antigens into a state of immune unresponsiveness. This conversion is successful in neonates: introduction of foreign antigens into a developing immune system prevents the system from responding further on to these antigens (1, 2). Recent evidence indicates that both in natural tolerance and in experimentally induced neonatal unresponsiveness maturing antigen-reactive thymocytes become either clonally deleted (3-8) or at least clonally silenced (9-11) .Induction of unresponsiveness in a mature peripheral T cell pool meets difficulties : receptor occupancy by antigens primarily induces sensitization rather than tolerization (12)(13)(14) . Therefore, most strategies attempt first to reduce the pool of immunocompetent peripheral T lymphocytes, and thereafter to induce unresponsiveness by exposing the regenerating (neonatal) immune system to antigen . In the first step, rather invasive techniques are used, such as whole body (15, 16) or total lymphoid irradiation (17), systemic application of antiproliferative drugs (18,19), or a combination of either of these methods.Evaluation of pretransplant transfusion effects have indicated that intravenous confrontation with allogeneic cells may induce specific immunosuppression rather than sensitization (20)(21)(22)(23)(24)(25)(26)(27)(28) Miller, Bevan, pioneered the veto cell concept . Accordingly, unlinked to the specificity of their own antigen receptor, veto cells paralyze in vitro the response of T cells reacting to antigens displayed by ...

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Section: Discussionmentioning

confidence: 92%

Induction of peripheral tolerance to class I major histocompatibility complex (MHC) alloantigens in adult mice: transfused class I MHC-incompatible splenocytes veto clonal responses of antigen-reactive Lyt-2+ T cells.

Heeg

Wagner

1990

The Journal of Experimental Medicine

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“…Anergy is thought to arise as the immature B cells leave the bone marrow and enter the periphery (12,42,43). If they meet Ags without the appropriate T cell help (CD40 Ligand), they are anergized or deleted.…”

Section: Discussionmentioning

confidence: 99%

B Cells from Mice Prematurely Expressing Human Complement Receptor Type 2 Are Unresponsive to T-Dependent Antigens

Birrell

Kulik

Morgan

et al. 2005

The Journal of Immunology

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Complement receptor type 2 (CR2/CD21), in association with CD19, plays an important role in enhancing mature B cell responses to opsonized Ags. We have shown that mice expressing a human CR2/CD21 (hCR2/CD21) transgene during the CD43+/CD25− late pro-B cell stage of B cell development demonstrate marked changes in subsequent B cell ontogeny. In the present study, we show that the humoral immune response to the T cell-dependent Ag, sheep RBC, is muted severely in a manner inversely proportional to B cell expression level of hCR2. Individual Ag-specific IgG isotypes vary in the degree to which they are affected but all are reduced while IgM titers are normal. A substantial reduction in germinal centers, both in size and frequency, in the spleens of immunized hCR2 transgenic mice demonstrates a failure to maintain germinal center reaction. However, both IgM expression levels and LPS-proliferative responses appear fully intact in B cells from hCR2-positive mice, suggesting that this alteration in B cell phenotype is different qualitatively from that of specific Ag-defined anergy models. These data suggest that the unresponsiveness to T-dependent Ags displayed by hCR2-positive B cells is linked to an increase in the level of stimulus required to propel the B cell into a fully activated state and thus a normal humoral immune response to Ags. We conclude that this phenotype and these mice may offer an additional means to dissect mechanisms underlying B cell tolerance and Ag responsiveness both in bone marrow and periphery.

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“…The role of the thymic vs. peripheral mechanisms in graft acceptance under both experimental and clinical circumstances has been controversial [66][67][68] . The prompt appearance of donor-derived leukocytes in the recipient thymus following organ transplantation 18 was of particular interest because of the strikingly tolerogenic effect in rodents of intrathymic inoculation of donor leukocytes 53 .…”

Section: Transplant Tolerance: Central or Peripheralmentioning

confidence: 99%

The lost chord: microchimerism and allograft survival

et al. 1996

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Recent evidence suggests that passenger leukocytes migrate after organ transplantation and produce persistent chimerism, which is essential for sustained survival of the allografts. Here, Thomas Starzl and colleagues argure that this hematolymphopoietic chimerism provides an important framework for the interpretation of basic and therapeutically oriented transplantataion research.Medawar's characterization of rejection 1 as a host-versus-graft (HVG) reaction (Fig. 1a) was the cornerstone of transplantation immunology. A decade later, this concept was transposed in the context of a graft-versus-host (GVH) reaction (Fig. 1b), in which histoincompatible hematolymphopoietic grafts rejected the immunologically defenseless recipients 2,3 . The resulting assumption that allograft acceptance or rejection could be understood by studying HVG or GVH immunologic responses in isolation led to prompt acceptance of the one-way in vitro tests of immune reactivity as 'minitransplant' surrogates. However, this assumption did not provide a blanket explanation for observations made in animal and human allograft recipients. The one-way paradigmUntil 1959, preparatory donor leukocyte infusion into cytoablated organ recipients was an expected natural extension of the neonatal tolerance model of Billingham, Brent and Medawar 4 and its adult cytoablation analogues 3 . However, when long-term survival of human kidney allografts was accomplished in a few sublethally irradiated recipients without donor leukocyte infusion, and then regularly without cytoreduction under continuous pharmacologic immunosuppression, the need either for chimerism or host preconditioning lost favor.The identification of 'passenger leukocytes' as the primary antigenic component of organs 6,7 led to the belief that their destruction by the host immune system was essential for organ engraftment. When these cells were found to be migratory 8 , including dendritic cells (DCs) 9 , their sensitization effects and presumed elimination at peripheral and intragraft sites was taken for granted. Bone marrow transplantationMajor histocompatibility complex (MHC)-restricted models of acquired tolerance were widely considered to have validated Burnet's prediction that developing lymphocytes could be purged of self-reactive cells before they achieved functional maturity, even following bone marrow transplantation. The alternative possibility that donor and recipient immunecell populations coexisted in neonatally tolerant animals in a mutually nonreactive state while retaining the ability to function collaboratively (e.g. in a joint immune response to infection) was abandoned when no direct experimental support could be found 10 it has since been learned that the outcome in the neonatal tolerance model is highly variable and that a state approaching permanent clonal deletion is uncommon 11 . Recently, it has been shown that the ability of donor-derived leukocyte subsets to proliferate in response to a skin graft challenge was a more critical determinant of neonatal tole...

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Cellular Mechanisms of Immunologic Tolerance

Cited by 493 publications

References 56 publications

Induction of peripheral tolerance to class I major histocompatibility complex (MHC) alloantigens in adult mice: transfused class I MHC-incompatible splenocytes veto clonal responses of antigen-reactive Lyt-2+ T cells.

Induction of peripheral tolerance to class I major histocompatibility complex (MHC) alloantigens in adult mice: transfused class I MHC-incompatible splenocytes veto clonal responses of antigen-reactive Lyt-2+ T cells.

B Cells from Mice Prematurely Expressing Human Complement Receptor Type 2 Are Unresponsive to T-Dependent Antigens

The lost chord: microchimerism and allograft survival

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