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PubMed2000

Role of genetic factors in organ-specific autoimmune diseases induced by manipulating the thymus or T cells, and not self-antigens.

There are accumulating demonstrations that manipulation of the T-cell immune system, such as elimination of a particular T-cell subpopulation from the periphery or removal of the thymus during a critical neonatal period, can elicit activation/expansion of pathogenic self-reactive T cells from the remaining T cells and produce a wide spectrum of organ-specific autoimmune diseases in otherwise normal mice or rats. The genetic makeup of the hosts appears to play a key role in determining which self-reactive T-cell clones are prone to be activated under such circumstances, since a comparable degree of the immunologic abnormality elicits autoimmune disease in different spectrums of organs, with different incidences and severities, depending on the mouse or rat strains used. These findings indicate that one aspect of natural immunologic self-tolerance is maintained by a T cell-mediated control of potentially pathogenic self-reactive T cells in the periphery, and that defective control, caused by environmental insults or genetic abnormalities, suffices to cause autoimmune disease; furthermore, in the presence of such a T-cell abnormality, host genetic factors including MHC and non-MHC genes may determine the specificity and intensity of the autoimmune responses, and consequently the phenotype of the autoimmune disease.

Animals↗
PubMed2003

Role of the thymus in the development of tolerance and autoimmunity towards the neuroendocrine system.

The thymus is the unique lymphoid organ inside which a confrontation occurs throughout life between neuroendocrine self-antigens and a recently evolved system with original recombination machinery driving random generation of immune response diversity. Through transcription of neuroendocrine genes in the thymus stromal network and expression of cognate receptors by immature T cells, the neuroendocrine system regulates early T cell differentiation. In addition and more specifically, intrathymic presentation of neuroendocrine self-antigens by, or in close association with, major histocompatibility complex (MHC) proteins is responsible for the establishment of central immune self-tolerance of neuroendocrine principles. All members of the insulin gene (INS) family are expressed in the thymus stroma according to a precise hierarchy and cell topography: IGF2 (thymic epithelial cells) > IGF1 (thymic macrophages) >> INS (thymic medullary epithelial cells and/or dendritic cells). Given this hierarchical pattern in gene expression, the protein IGF-2 is more tolerated than INS. Igf2 transcription is defective in the thymus of bio-breeding (BB) rat, one animal model of type 1 diabetes (T1DM). This thymus-specific defect in Igf2 expression may explain both the absence of central tolerance to INS-secreting beta cells and the lymphopenia (including lack of regulatory RT6(+) T cells) in diabetes-prone BB rats. INS B:9-23 and the homologous sequence of IGF-2 compete for binding to DQ8, an MHC class II allele conferring major susceptibility to T1DM. In young DQ8(+) T1DM patients, INS B:9-23 presentation by DQ8 elicits a dominant IFN-gamma secretion by isolated PBMCs, whereas presentation of the IGF-2 self-antigen promotes a dominant regulatory interleukin-10 secretion. These data demonstrate that opposite immune responses are driven by MHC presentation of a self-antigen (here, IGF-2) and an autoantigen (INS, as "altered" self). The important tolerogenic properties of thymic self-antigens deserve now to be exploited for prevention and/or cure of devastating autoimmune diseases such as T1DM.

Animals↗
PubMed2000

Development of myelin oligodendrocyte glycoprotein autoreactive transgenic B lymphocytes: receptor editing in vivo after encounter of a self-antigen distinct from myelin oligodendrocyte glycoprotein.

We explored mechanisms involved in B cell self-tolerance against brain autoantigens in a double-transgenic mouse model carrying the Ig H-chain (introduced by gene replacement) and/or the L-chain kappa (conventional transgenic) of the mAb 8.18C5, specific for the myelin oligodendrocyte glycoprotein (MOG). Previously, we demonstrated that B cells expressing solely the MOG-specific Ig H-chain differentiate without tolerogenic censure. We show now that double-transgenic (THkappa(mog)) B cells expressing transgenic Ig H- and L-chains are subjected to receptor editing. We show that in adult mice carrying both MOG-specific Ig H- and L-chains, the frequency of MOG-binding B cells is not higher than in mice expressing solely the transgenic Ig H-chain. In fact, in THkappa(mog) double-transgenic mice, the transgenic kappa(mog) L-chain was commonly replaced by endogenous L-chains, i.e., by receptor editing. In rearrangement-deficient RAG-2(-) mice, differentiation of THkappa(mog) B cells is blocked at an immature stage (defined by the B220(low)IgM(low)IgD(-) phenotype), reflecting interaction of the autoreactive B cells with a local self-determinant. The tolerogenic structure in the bone marrow is not classical MOG, because back-crossing THkappa(mog) mice into a MOG-deficient genetic background does not lead to an increase in the proportion of MOG-binding B cells. We propose that an as yet undefined self-Ag distinct from MOG cross-reacts with the THkappa(mog) B cell receptor and induces editing of the transgenic kappa(mog) L-chain in early immature B cells without affecting the pathogenic potential of the remaining MOG-specific B cells. This phenomenon represents a particular form of chain-specific split tolerance.

Animals↗
PubMed1996

Self determinant selection and acquisition of the autoimmune T cell repertoire.

Autologous proteins are continuously processed and presented in the form of peptides associated with self major histocompatibility (MHC) molecules at the surface of antigen-presenting cells for interaction with autoreactive T cells. During thymic selection, the presentation of self peptides is an essential element in the establishment of the T cell repertoire. Developing T cells which recognize self peptide/self MHC complexes with sufficient affinity are clonally deleted. However, we and others have recently demonstrated that a variety of self peptides, despite their high binding affinity to MHC molecules, never reach the threshold of presentation to ensure negative selection (cryptic self peptides). This mechanism may have been selected to avoid excessive purging of T cell repertoire during ontogeny. However, T cells directed to cryptic self determinants represent a continuous threat for the initiation of autoimmunity in adults. Supporting this view, recent studies have documented the involvement of cryptic self peptide presentation in different autoimmune diseases. In this article, we examine the factors that govern the selection of self peptides for presentation to autoreactive T cells in vivo and discuss their contribution to both the induction and the maintenance of self tolerance. In addition, we analyze the mechanisms by which the hierarchy of determinants on a self protein can be disrupted, thereby leading to the presentation of previously cryptic self peptides and the induction of an autoimmune T-cell-mediated process.

Animals↗
PubMed2006

Self-reactive CD4+ T cells and B cells in the blood in health and autoimmune disease: increased frequency of thyroglobulin-reactive cells in Graves' disease.

The mechanisms underlying activation of potentially self-reactive circulating B cells and T cells remain unclear. We measured the uptake of a self-antigen, thyroglobulin, by antigen presenting cells, and the subsequent proliferation of CD4(+) T cells and B cells from healthy controls and patients with autoimmune thyroiditis. In Hashimoto's thyroiditis, B cells bound increased amounts of thyroglobulin in a complement- and autoantibody-dependent manner, and the thyroglobulin-elicited proliferation of CD4(+) T cells and B cells was complement dependent. Increased proportions of Tg-responsive CD4(+) T cells and B cells were found in patients with Graves' disease. Notably, both patient groups and healthy controls exhibited higher proliferative responses to thyroglobulin than to a foreign recall antigen, tetanus toxoid. Our results suggest that self-tolerance can be broken by exposure of circulating lymphocytes to high local concentrations of self-antigen, and that complement plays a role in the maintenance of autoimmune processes, at least in Hashimoto's thyroiditis.

Autoantibodies↗
PubMed1991

Prevention of syngeneic graft-versus-host disease by recovery of thymic microenvironment after cyclosporine.

Following a course of cyclosporine, syngeneic rat radiation chimeras consistently develop a GVHD-like syndrome. Correlation of the thymic immunopathology with conditions leading to syngeneic graft-versus-host disease (sGVHD) suggested the hypothesis that reconstitution of the normal thymic microenvironment after CsA is necessary for self-tolerance. When thymic regeneration is impaired, as in rats receiving previous mediastinal irradiation, then self-reactive effector cells are not regulated and proceed to damage the target tissues. Alternately, it could be argued that the observed thymic abnormalities are irrelevant to sGVHD. To test the primary hypothesis, post-CsA thymic reconstitution was prevented by total thymectomy in unirradiated rats. These rats consistently developed acute type sGVHD seen at 7 and 21 days post-CsA while rats from the CsA-treated sham thymectomy control group failed to develop sGVHD. Because thymectomy prior to CsA blocks sGVHD, most likely the peripheral effector cells in the post-CsA thymectomy group were derived from the CsA-altered thymus. The absence of sGVHD in the sham group indicates that the thymus led to active regulation of these cells after stopping CsA. If regeneration of the thymus restored only negative selection, then the sham thymectomy group should have also developed sGVHD. Flow cytometry and morphology of the spleen and lymph nodes demonstrated that the thymectomized rats, like CsA-treated radiation chimeras, experienced a significant delay in maturation of T cells following CsA. In contrast to the usual model in radiation chimeras, however, the post-CsA thymectomized rats did not convert to chronic type sGVHD. The importance of an abnormal thymus for this transition was confirmed in syngeneic radiation chimeras. Thymectomy after CsA in these rats also blocked the rapid transition to chronic sGVHD.

Acute Disease↗
PubMed1992

Tolerance to host minor histocompatibility antigens after allogenic bone marrow transplantation. Specific donor-host unresponsiveness is maintained by peripheral tolerizing cells.

The development of graft-host tolerance after allogeneic bone marrow (BM) transplantation is more demanding than the acquisition of self-tolerance because both donor-derived mature T cells and immature thymocytes encounter host Ag. The mechanism involved in tolerization of mature T cells, contained in unmanipulated BM, remains undefined. In previous experiments, we showed in vivo unresponsiveness to host minor histocompatibility Ag (MiHA) in immunocompetent chimeras obtained after MiHA-incompatible BM transplantation. In this study, we wanted to determine: first, what was the specificity of this graft-host unresponsiveness, and second, whether peripheral cells were involved in tolerization? LP recipients were irradiated (9, 5 Gy), injected with 10(7) undepleted BM cells from B10 donors and studied 100 to 150 days later. (B10-->LP) chimeras were immunized in vivo and restimulated in vitro with cells displaying one or multiple incompatible MiHA. In bulk culture experiments, chimeras demonstrated specific CTL unresponsiveness to host MiHA but responded normally to third party MiHA. In limiting dilution analysis conditions, chimeras showed a profound deficit, but not a complete absence of anti-host CTL precursor. Studies with congenic stimulators/targets showed that graft-host tolerance was induced against both immunodominant (e.g., H-3.2) and nonimmunodominant (e.g., H-8.2) MiHA although at the CTL precursor level, it was more complete against the former. Furthermore, chimera spleen cells inhibited the generation of CTL activity against host- and donor-type MiHA but not against third party Ag. This specific suppressor activity was not T cell dependent, and was mediated by radiosensitive cells that are not found in freshly explanted organs from normal mice. Taken together, our results suggest that peripheral tolerization can be a remarkably efficient process to maintain tolerance to MiHA after BM transplantation. Thus, peripheral tolerizing mechanisms may contribute not only to the induction of tolerance to Mls superantigens or to the product of transgenes (if expressed at high levels) but also to a wide array of MiHA.

Animals↗
PubMed1985

Limiting dilution analysis of induced unresponsiveness to trinitrophenyl: increased suppression of cytotoxic T precursor cells at unchanged frequencies.

In this paper we address the problem of tolerance in the immune system. We are discussing results of experiments that we designed to distinguish between the two major alternative hypotheses that have been invoked for immunological tolerance: clonal deletion/anergy versus suppression. These alternative hypotheses make essentially different predictions with respect to the frequencies of lymphocytes that react with antigens to which the immune system is tolerant: clonal deletion models predict reduced frequencies, whereas in suppression models precursors of effector cells are postulated to occur at frequencies similar to the nontolerant situation. We investigate these questions by limiting dilution analyses of cytotoxic T cell precursors (CTLP), using two different ways to activate them into functional cytotoxic cells (CTL): polyclonally by Concanavalin A (ConA) and specifically by antigen. Tolerance should be apparent in either protocol since neither antigen nor ConA usually activates self-reactive cytotoxic cells. Moreover, in addition to providing information on precursor frequencies, the multihit results usually obtained in limiting dilution experiments of ConA activated T cells allow the determination of quantitative and qualitative parameters of suppression. In addition, clonal anergy situations could be expected to become apparent by a differential sensitivity of precursors to activation with ConA and with antigen. As experimental system we chose the induced unresponsiveness of mice to trinitrophenyl (TNP) achieved by intravenous injection of reactive trinitrobenzenesulfonic acid (TNBS) and measured in a primary cytotoxic response to TNP-coupled syngeneic cells (TNP-SC). An equally specific but perhaps not identical form of unresponsiveness is induced by coupling the responder cell population with TNBS in vitro. Although we do not propose that this model ideally reflects all aspects of self tolerance, we think that in this particular system of induced unresponsiveness the antigen becomes associated with the surfaces of a large proportion of the cells of the body. Therefore, tolerance to widely expressed cell surface determinants might be quite adequately "simulated" by this experimental unresponsiveness. In our limiting dilution experiments we can distinguish between frequent and infrequent cytotoxic precursors which correspond to virgin and memory cells, respectively. For the frequent CTLP the situation is quite clear: they occur at essentially equal frequencies in normal and tolerant mice, as demonstrated by their reactivity to antigen at low cell densities. However, they are under the influence of a suppressive activity which is strongly increased when compared to that of normal mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti-OX40 and anti-4-1BB monoclonal antibodies induces T cell-mediated protective immunity in Her-2/neu transgenic mice.

Tumor cells express tumor-associated antigens (TAAs), which can serve as targets for the immune system. However, the majority of TAAs are overexpressed products of normal cellular genes; as such, self-tolerance mechanisms have hindered their use for the induction of effective antitumor responses. One such normal self-protein is the growth factor receptor Her-2/neu, which is overexpressed in 25-35% of all mammary carcinomas in humans. In previous studies, we have demonstrated that Her-2/neu mice are functionally tolerant to neu antigens and contain only a low avidity T-cell repertoire to neu antigens. However, this residual low-avidity T-cell repertoire has antitumor activity. In this study, we compared the immune responses of Her-2/neu mice immunized with dendritic cells (DCs) pulsed with soluble neu protein or with apoptotic tumor cells. Analysis of the antitumor response shows that Her-2/neu mice vaccinated with DCs pulsed with Her-2/neu antigens retard tumor growth; however, vaccination with DCs pulsed with apoptotic tumor cells induces a stronger antitumor effect. Administration of multiple immunizations in combination with the costimulatory agonist anti-OX40 or anti-4-1BB MAb significantly enhanced the immune responses in these mice, resulting in complete tumor rejection if the tumor burden was small and substantial tumor reduction with a larger tumor burden. These results have important implications for the design of tumor vaccination strategies, suggesting that the use of vaccines that stimulate a broad immune response in combination with costimulatory molecules as immunomodulators could significantly improve the antitumor immune response in tolerant hosts.

Animals↗
PubMed2005

Linking signalling pathways, thymic stroma integrity and autoimmunity.

Medullary thymic epithelial cells (mTECs) are indispensable for self-tolerance to peripheral organs by virtue of their expression of a host of tissue-restricted self-antigens. The full extent of this promiscuous gene expression is confined to functionally mature mTECs. Consequently, any interference with signalling pathways directing the differentiation and/or proliferation of this mature subset will affect the scope of central tolerance and potentially predispose to autoimmunity. In a recent study, tumour necrosis factor receptor-associated factor 6 (TRAF6) has been identified as an essential component of a new signalling pathway directing mTEC development.

Animals↗
PubMed2001

CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade.

Immune regulatory CD4(+)CD25(+) cells play a vital role in the induction and maintenance of self-tolerance and are essential for T cell homeostasis and the prevention of autoimmunity. Induction of tolerance to allogeneic donor grafts is a clinically desirable goal in bone marrow and solid organ transplantation. To determine whether CD4(+)CD25(+) cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4(+) T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte-associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo. CD4(+)CD25(+) T cells were found to be potent regulators of alloresponses. Depletion of CD4(+)CD25(+) T cells from the CD4(+) responder population completely abrogated ex vivo tolerance induction to alloantigen as measured by intact responses to alloantigen restimulation in vitro and in vivo. Addback of CD4(+)CD25(+) T cells to CD4(+)CD25(-) cultures restored tolerance induction. These data are the first to indicate that CD4(+)CD25(+) cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.

Abatacept↗
PubMed1986

The Florey lecture, 1986. The regulatory biology of antibody formation.

The regulatory biology of antibody formation entered a new phase of study with the development of selective theories of immunity. The discovery of the 'one cell - one antibody' dogma and the demonstration that only a small minority of B cells possessed receptors specific for a given antigen were consistent with Burnet's clonal selection hypothesis, which was later formally proven by preparing antigen-specific lymphocytes and inducing clonal activation in vitro. Clonal analysis has aided precise study of immunoregulation for both B and T lymphocytes. Clonal activation of B cells in the absence of T cells is now possible with high cloning efficiency. It requires the combined action of certain antigens and growth factors, collectively termed B-cell stimulatory factors (BSFS). Single cell analysis has shown that most BSFS so far tested, in contrast to most claims in the literature, possess the capacity (in synergy with antigen) to: stimulate B cells out of the G0 phase into active cell cycle; promote sequential mitotic divisions; and induce differentiation to active secretory status. This is clearly true for IL-1, IL-2, and BSF-p2. These multiple actions resemble those of the colony-stimulating factors in haemopoiesis. Regulation of antibody production by T lymphocytes can also be profitably analysed in clonal systems. The immunoregulatory problem of tolerance can also be analysed by means of clonal techniques. Studies are summarized which indicate that T-cell-mediated suppression and functional silencing of toleragen-specific lymphocytes are both cooperatively involved in many tolerance models. For the B lymphocyte, tolerance can be induced without an actual deletion of the cell involved; rather, the tolerant cell appears to have received and stored a negative signal, rendering it unresponsive to normally immunogenic stimuli. Thus, a state termed 'clonal anergy' has been induced within the cell. Functional clonal deletion has also been noted in several models to T-lymphocyte tolerance, but here it is not known whether clonal anergy or actual death of the relevant cell is at work. Self-tolerance sufficient to be consistent with good health need not mean a total absence of cells with any degree of self-reactivity. Indeed, it is clear that some B cells capable of forming antibody with some degree of affinity for self-constituents exist in the body, and can be activated, for example by lipopolysaccharide. The requirement is to limit the amount, affinity and duration of autoantibody production. A model suggesting how this may be achieved is presented.

Animals↗
PubMed1995

Genetic background and environment contribute synergistically to the onset of autoimmune diseases.

Autoimmune diseases result from the breakdown of "self" tolerance. Environmental factors appear to be responsible for triggering this errant immune response, directed against self-tissue determinants, only when a susceptible genetic background is present in an individual. Autoimmune diseases, normally characterized by their association with certain HLA alleles, also share other features: the presence of autoantibodies, autoreactive T lymphocytes, and an intermittent clinical course of exacerbations and remissions. In cases of organ-specific diseases, as well as in cases of multi-system autoimmune diseases, viruses are increasingly implicated as such environmental triggers. Current molecular biology techniques have permitted a fine dissection of the genetic background of susceptible individuals and have enabled a more complete characterization of the immunocompetent cells involved in this autoaggression. Molecular approaches will soon allow us to pinpoint the characteristics of the environmental stimuli, so that protective strategies could be formulated to spare susceptible individuals from their ill effects.

Autoimmune Diseases↗
PubMed2005

Viruses and autoimmunity.

Viruses have been suspected as causes and contributors of human autoimmune diseases (AID), although direct evidence for the association is lacking. However, several animal models provide strong evidence that viruses can induce AIDs as well as act to accelerate and exacerbate lesions in situations where self-tolerance is broken. Many models support the hypothesis by acting as molecular mimics that stimulate self-reactive lymphocytes. Mimicry alone is usually inadequate and with human AID, no compelling evidence supports a role for viruses that are acting as molecular mimics. Alternative mechanisms by which viruses participate in autoimmunity are non-specific, involving a mechanistically poorly understood process termed bystander activation or perhaps viral interference with regulatory cell control systems. This review briefly discusses examples where viruses are involved, taking the viewpoint that molecular mimicry is over emphasized as a critical mechanism during AID pathogenesis.

Animals↗
PubMed2006

Viruses and autoimmunity.

Viruses have been suspected as causes and contributors of human autoimmune diseases (AID), although direct evidence for the association is lacking. However, several animal models provide strong evidence that viruses can induce AIDs as well as act to accelerate and exacerbate lesions in situations where self-tolerance is broken. Many models support the hypothesis by acting as molecular mimics that stimulate self-reactive lymphocytes. Mimicry alone is usually inadequate and with human AID, no compelling evidence supports a role for viruses that are acting as molecular mimics. Alternative mechanisms by which viruses participate in autoimmunity are non-specific, involving a mechanistically poorly understood process termed bystander activation or perhaps viral interference with regulatory cell control systems. This review briefly discusses examples where viruses are involved, taking the view point that molecular mimicry is over emphasized as a critical mechanism during AID pathogenesis.

Animals↗
PubMed1999

CD1-reactive natural killer T cells are required for development of systemic tolerance through an immune-privileged site.

Systemic tolerance can be elicited by introducing antigen into an immune-privileged site, such as the eye, or directly into the blood. Both routes of immunization result in a selective deficiency of systemic delayed type hypersensitivity. Although the experimental animal model of anterior chamber-associated immune deviation (ACAID) occurs in most mouse strains, ACAID cannot be induced in several mutant mouse strains that are coincidentally deficient in natural killer T (NKT) cells. Therefore, this model for immune-privileged site-mediated tolerance provided us with an excellent format for studying the role of NKT cells in the development of tolerance. The following data show that CD1-reactive NKT cells are required for the development of systemic tolerance induced via the eye as follows: (a) CD1 knockout mice were unable to develop ACAID unless they were reconstituted with NKT cells together with CD1(+) antigen-presenting cells; (b) specific antibody depletion of NKT cells in vivo abrogated the development of ACAID; and (c) anti-CD1 monoclonal antibody treatment of wild-type mice prevented ACAID development. Significantly, CD1-reactive NKT cells were not required for intravenously induced systemic tolerance, thereby establishing that different mechanisms mediate development of tolerance to antigens inoculated by these routes. A critical role for NKT cells in the development of systemic tolerance associated with an immune-privileged site suggests a mechanism involving NKT cells in self-tolerance and their defects in autoimmunity.

Animals↗
PubMed2003

Role of CD41CD251 regulatory T cells from naive host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide.

BACKGROUND: Immunization with allo-major histocompatibility complex peptide induces operational tolerance, whereas thymectomy abrogates this effect. We hypothesized that recent thymic emigrants with regulatory function are important in the induction of acquired transplant tolerance in this system. METHODS: In this study, we examined the possibility of restoring transplant tolerance to thymectomized (TMX) ACI recipients with concomitant adoptive transfer of syngeneic T cells indirectly primed with a single immunodominant Wistar Furth allo-major histocompatibility complex class I peptide (peptide 5, residues 93-109) and unmodified thymocytes or CD4+CD25+ thymic T cells. RESULTS: Co-transfer of in vivo allopeptide-primed T cells and naive syngeneic thymic T cells on day -7 restored permanent acceptance of cardiac allografts to 70% of transiently antilymphocyte serum-immunosuppressed TMX recipients. Similarly, the adoptive transfer of allopeptide-primed T cells led to 100% donor-specific permanent graft acceptance among transiently antilymphocyte serum-immunosuppressed TMX recipients with renal subcapsular syngeneic thymic grafts. To demonstrate the role of regulatory T cells among new thymic emigrants in the induction of tolerance, we showed that the co-transfer of CD4+CD25+ but not CD4+CD25- thymic T cells with allopeptide-primed syngeneic T cells restored tolerance to TMX recipients. It seems that the induction of transplant tolerance in this system is dependent on the presence of CD4+CD25+ regulatory T cells among the recent thymic emigrants. CONCLUSIONS: This study suggests that CD4+CD25+ regulatory T cells specific for the induction of transplant tolerance are similar in origin, phenotype, and function to those involved in the maintenance of self-tolerance and the prevention of autoimmunity.

Adoptive Transfer↗
PubMed2001

Intravenous injection of apoptotic leukocytes enhances bone marrow engraftment across major histocompatibility barriers.

Cross-tolerization of T lymphocytes after apoptotic cell uptake by dendritic cells may be involved in self-tolerance maintenance. Furthermore, immunosuppressive properties are attributed to apoptotic cells. This study evaluated the consequences of apoptotic leukocyte administration in a restrictive engraftment model of murine bone marrow (BM) transplantation. Sublethally irradiated recipients received a limited number of allogeneic BM, with or without irradiated apoptotic leukocytes of different origins. No graft-versus-host disease was observed. Whereas only a low proportion of mice receiving BM cells alone engrafted, addition of apoptotic irradiated leukocytes, independently of the origin (donor, recipient, third-party mice, as well as xenogeneic peripheral blood mononuclear cells), significantly enhanced engraftment. Similar results were obtained after infusion of leukocytes rendered apoptotic by UVB irradiation or by anti-Fas monoclonal antibody stimulation, thus confirming the role of apoptotic cells in engraftment facilitation. Overall, these results suggest that apoptotic leukocytes can nonspecifically facilitate allogeneic BM engraftment. Such a simple approach could be of interest in BM transplantation settings involving an important HLA donor/recipient disparity, a T-cell-depleted graft, or reduced conditioning regimen intensity.

Animals↗