scholarly journals Transplantation Tolerance Induced in Humans at the Fetal or the Neonatal Stage

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
Jean-Louis Touraine ◽  
Kamel Sanhadji
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
Conditioning Regimen ◽  
Host Cells ◽  
Positive Interactions ◽  
Transplantation Tolerance ◽  
Cell Repertoire ◽  
Clonal Deletion

Patients transplanted with HLA-mismatched stem cells from fetal livers develop transplantation tolerance to donor antigens. Engraftment needs no conditioning regimen prior to transplantation in neonates with severe combined immunodeficiency disease or in human fetal patients having not yet developed any immune maturity, especially T-cell differentiation. The chimeric patients have donor-derived T lymphocytes which progressively demonstrate positive interactions with other host cells. They also can be shown to be tolerant toward both host and donor antigens. The latter tolerance relies upon clonal deletion from the T-cell repertoire, and it results from the contact between thymocytes of donor origin and dendritic cells or macrophages also deriving from donor stem cells. The former tolerance does not imply clonal deletion of T-cells with host reactivity. Numerous T-cells recognizing the allogeneic, host-type antigens are identified in these patients, but these cells are anergized, following interaction with epithelial cells of the host thymus. Induction of transplantation tolerance at the fetal stage requires minimal engraftment only; in the future it will be possible to further amplify the clinical benefit, using additional cell transplants after birth.

scholarly journals Dysfunctional cytokine production by host-reactive T-cell clones isolated from a chimeric severe combined immunodeficiency patient transplanted with haploidentical bone marrow

Blood ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1944-1953 ◽  
Author(s):  
R Bacchetta ◽  
R Parkman ◽  
M McMahon ◽  
K Weinberg ◽  
M Bigler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Severe Combined Immunodeficiency ◽  
Host Cells ◽  
Combined Immunodeficiency ◽  
Clonal Deletion ◽  
T Cell Clones ◽  
Cell Clones

We have investigated the mechanism of tolerance in a patient with severe combined immunodeficiency (SCID) transplanted with HLA-haploidentical, T cell-depleted bone marrow cells obtained from the mother. At 4 years after transplantation, T cells, natural killer (NK) cells, and a small percentage (2%) of B cells were found to be of donor origin, whereas monocytes and the majority of B cells remained of host origin. In primary mixed lymphocyte cultures (MLC), the engrafted T cells of the donor did not proliferate in response to the host cells, whereas untransplanted donor T cells showed good proliferative responses. However, CD4+ and CD8+ T-cell clones of donor origin with specificity for class II and class I HLA determinants of the host were isolated. CD8+, host-reactive T-cell clones displayed normal cytotoxic activity after stimulation with the host cells, but proliferative responses of CD4+, host-reactive T-cell clones were considerably reduced. In addition, both CD8+ and CD4+, host-reactive T-cell clones produced very low to undetectable levels of interleukin-2 (IL-2), IL-4, IL-5, IL-10, interferon-gamma, and granulocyte-macrophage colony-stimulating factor after specific antigenic activation, which may be responsible for their nonresponsive state in vivo. Expression of the CD3 zeta subunit of the T-cell receptor (TcR) was normal, and after stimulation via CD3, Raf-1 and p42 mitogen activated protein (MAP) kinase were phosphorylated, indicating that this part of the signaling pathway after triggering of the TcR/CD3 complex is present. These results, together with our previous observation that dysfunctional, host-reactive T-cell clones can be isolated in SCID patients transplanted with fetal liver stem cells, demonstrate that lack of clonal deletion of host-reactive T cells is a general phenomenon after HLA-mismatched stem cell transplantation.

scholarly journals Rat T cell response to superantigens. I. V beta-restricted clonal deletion of rat T cells differentiating in rat-->mouse chimeras.

1994 ◽  
Vol 179 (1) ◽  
pp. 57-62 ◽  
Author(s):  
C D Surh ◽  
D P Gold ◽  
S Wiley ◽  
D B Wilson ◽  
J Sprent
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
T Cell Response ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
Specific Reactivity

T cells of mice display V beta-specific reactivity for a spectrum of mouse mammary tumor virus (Mtv) antigens; confrontation with these antigens during ontogeny causes substantial "holes" in the T cell repertoire. Since endogenous Mtv antigens are rare in other species, the question arises whether V beta-specific recognition of Mtv antigens is unique to mice. To examine this question, rat T cells were allowed to differentiate from stem cells in severe combined immunodeficiency (SCID) mice. These rat-->mouse xenochimeras were prepared under a variety of conditions. The results show that rat T cells are strongly reactive to mouse Mtv antigens, both in terms of tolerogenicity and immunogenicity. In fact, the V beta specificity of rat and mouse T cells for Mtv antigens is almost indistinguishable.

T cell repertoire and clonal deletion of Mtv superantigen-reactive T cells in mice lacking CD4 and CD8 molecules

1995 ◽  
Vol 25 (7) ◽  
pp. 2115-2118 ◽  
Author(s):  
Josef M. Penninger ◽  
Marco W. Schilham ◽  
Emma Timms ◽  
Valerie A. Wallace ◽  
Tak W. Mak
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Clonal Deletion

scholarly journals In vitro correlate for a clonal deletion mechanism of immune response gene-controlled nonresponsiveness.

1983 ◽  
Vol 157 (3) ◽  
pp. 998-1005 ◽  
Author(s):  
N Ishii ◽  
Z A Nagy ◽  
J Klein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Response Gene ◽  
Mouse Strains ◽  
Single Chain ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Class Ii Mhc ◽  
Antigen Presenting

We used T cell-antigen-presenting cell (APC) combinations from two pairs of recombinant mouse strains, B10.A(4R)-B10.A(2R) and B10.S(7R)-B10.S(9R) (abbreviated 4R, 2R, 7R, 9R, respectively), which differ from each other only in the nonexpression vs. expression of cell-surface E molecules, to study the mechanism of the Ir gene-controlled (E-restricted) response to the terpolymer poly(glu51lys34tyr15) (GLT). No response to GLT occurred when the APC were from E-nonexpressor strains 4R and 7R. When APC from E-expressor strains were used and alloreactivity against the incompatible E molecules was removed by BUdR + light treatment, 7R T cells responded to GLT presented by 9R APC, but 4R T cells failed to respond to GLT presented by 2R APC. However, 4R T cells mounted a proliferative response to GLT presented by fully allogeneic 5R or 9R APC. The latter response was completely abolished by the depletion of cells alloreactive against 2R and 5R or 2R and 9R. Since removal of alloreactivity against 5R plus 9R did not affect the response of 4R T cells to GLT presented by either 5R or 9R cells, we conclude that the 4R T cells generated in response to GLT cross-react with the additional incompatibility presented by 2R cells, that is, the Ek beta chain. In contrast, 7R T cells recognizing GLT presented by 9R APC do not cross-react with Ek beta. These results demonstrate that "blind spots" in the T cell repertoire produced by depletion of cells alloreactive against a single chain of a class II MHC molecule can render a strain nonresponsive to a synthetic polypeptide antigen, and that this nonresponsiveness corresponds to that attributed to the MHC-linked Ir genes.

In Vivo T-Lymphocyte Tolerance in the Absence of Thymic Clonal Deletion Mediated by Hematopoietic Cells

Blood ◽  
1999 ◽  
Vol 93 (11) ◽  
pp. 3856-3862 ◽  
Author(s):  
Joost P.M. van Meerwijk ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
Negative Selection ◽  
Apoptotic Cell ◽  
Hematopoietic Cells ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
Clonal Deletion

Abstract Thymic negative selection renders the developing T-cell repertoire tolerant to self-major histocompatability complex (MHC)/peptide ligands. The major mechanism of induction of self-tolerance is thought to be thymic clonal deletion, ie, the induction of apoptotic cell death in thymocytes expressing a self-reactive T-cell receptor. Consistent with this hypothesis, in mice deficient in thymic clonal deletion mediated by cells of hematopoietic origin, a twofold to threefold increased generation of mature thymocytes has been observed. Here we describe the analysis of the specificity of T lymphocytes developing in the absence of clonal deletion mediated by hematopoietic cells. In vitro, targets expressing syngeneic MHC were readily lysed by activated CD8+ T cells from deletion-deficient mice. However, proliferative responses of T cells from these mice on activation with syngeneic antigen presenting cells were rather poor. In vivo, deletion-deficient T cells were incapable of induction of lethal graft-versus-host disease in syngeneic hosts. These data indicate that in the absence of thymic deletion mediated by hematopoietic cells functional T-cell tolerance can be induced by nonhematopoietic cells in the thymus. Moreover, our results emphasize the redundancy in thymic negative selection mechanisms.

Analysis of T-Cell Repertoire before and 21 Days after Autologous Peripheral Blood Stem Cell Transplantation for Systemic Sclerosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1648-1648
Author(s):  
Albert D. Donnenberg ◽  
Vera S. Donnenberg ◽  
Thomas A. Medsger ◽  
Diane M. BuchBarker ◽  
Dawn M. Betters ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Systemic Sclerosis ◽  
T Cell ◽  
Peripheral Blood Stem Cell ◽  
Conditioning Regimen ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Autologous Pbsct ◽  
Blood Stem Cell Transplantation

Abstract The goal of autologous peripheral blood stem cell transplantation (PBSCT) in autoimmune diseases is to ablate the clones of autoimmune lymphocytes. We evaluated the T-cell repertoire in 5 patients (pts) with systemic sclerosis (SSc) who received T-depleted (mean T-cell reduction, 5.2 log) autologous PBSCT after a conditioning regimen of cyclophosphamide (200–400 mg/m2/day x 5), fludarabine (25 mg/m2/day x 5), and rabbit anti-thymocyte globulin (2.5 mg/kg/day x 3). One pt has had a recurrence of SSc at 12 months after PBSCT; the other pts are progression-free at 4.9+, 5.1+, 6.5+ and 11.5+ months, respectively, after PBSCT. We used 5-color flow cytometry to assess T-cell receptor V-beta repertoire in CD4+ and CD8+ peripheral T-cells susbsetted into central memory (CM; CD45RA−/CD27+), naïve (N, CD45RA+/CD27+), effector/memory (EM; CD45RA−/CD27−) and effector (E; CD45RA−/CD27−) populations. Pts were studied before and at 21 days after PBSCT. The pt with recurrence of SSc had 2 large expansions in CD4+ T-cells (Vbeta 1 and 14) before PBSCT, which were conserved and amplified at 21 days post PBSCT. These expansions were limited to the EM and E populations before PBSCT but were evident in all except the E subset at 21 days after PBSCT. Of the remaining 4 pts, none had evidence of CD4 expansions, and 3 had multiple CD8 expansions before PBSCT. In all cases, the expansions were limited to the EM and E populations. None of these T-cell restrictions were conserved in the 21-day post-PBSCT sample. These data suggest that EM and E T-cell expansions present before PBSCT in pts with SSc can be ablated by an immunosuppressive conditioning regimen. Although our observations require confirmation in a larger series of pts, the conservation of restrictions at 21 days after PBSCT may be a poor prognostic sign for efficacy of autologous PBSCT in SSc.

In vitro development of murine T cells from prethymic and preliver embryonic yolk sac hematopoietic stem cells

Development ◽  
1991 ◽  
Vol 113 (4) ◽  
pp. 1315-1323 ◽  
Author(s):  
C.P. Liu ◽  
R. Auerbach
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Fetal Liver ◽  
Critical Factor ◽  
Yolk Sac ◽  
Cell Repertoire ◽  
Hematopoietic Stem ◽  
Developmental Potential

Mature T cells are derived from prethymic stem cells, which arise at one or more extrathymic sites and enter and differentiate in the thymus. The nature of these prethymic stem cells is a critical factor for the formation of the T-cell repertoire. Although the bone marrow of adult mice can provide such stem cells, their origin during murine embryogenesis is still undetermined. Among potential sites for these progenitor cells are the fetal liver and the embryonic yolk sac. Our studies focus on the yolk sac, both because the yolk sac appears earlier than any other proposed site, and because the mammalian yolk sac is the first site of hematopoiesis. Although it has been shown that the yolk sac in midgestation contains stem cells that can enter the thymic rudiment and differentiate toward T-cell lineage, our aim was to analyze the developmental potential of cells in the yolk sac from earlier stages, prior to the formation of the liver and any other internal organ. We show here that the yolk sac from 8- and 9-day embryos (2–9 and 13–19 somites, respectively) can reconstitute alymphoid congenic fetal thymuses and acquire mature T-cell-specific characteristics. Specifically, thymocytes derived from the early embryonic yolk sac can progress to the expression of mature T lymphocyte markers including CD3/T-cell receptor (TCR), CD4 and CD8. In contrast, we have been unable to document the presence of stem cells within the embryo itself at these early stages. These results support the hypothesis that the stem cells capable of populating the thymic rudiment originate in the yolk sac, and that their presence as early as at the 2- to 9-somite stage may indicate that prethymic stem cells found elsewhere in the embryo at later times may have been derived by migration from this extra-embryonic site. Our experimental design does not exclude the possibility of multiple origins of prethymic stem cells of which the yolk sac may provide the first wave of stem cells in addition to other later waves of cells.

scholarly journals Acquired Mls-1a-like clonal deletion in Mls-1b mice.

1992 ◽  
Vol 175 (2) ◽  
pp. 453-460 ◽  
Author(s):  
M Papiernik ◽  
C Pontoux ◽  
S Gisselbrecht
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Genetic Transmission ◽  
Cd8 Cells ◽  
High Level

BALB/c mice (H-2d, Mls-1b) from one colony progressively modify their T cell repertoire during aging, by deleting T cells that express products of the V beta 6 and V beta 8.1 genes of the T cell receptor. Clonal deletion occurs only in 50% of mice between 27 and 43 wk of age, affecting thymus, spleen, and lymph node T cells. The phenomenon is progressive and seems to affect nearly all thymuses between 14 and 19 wk of age. CD4+CD8- mature T cells are more affected than CD4-CD8+ cells. In the thymus, deletion occurs at the stage of immature J11d+ cells expressing a high level of V beta 6, while J11d+V beta 6low-expressing cells are not modified. Clonal deletion is thus an early phenomenon that deletes cells of the immature generative compartment in the thymus. This Mls-1a-like clonal deletion is associated neither with the expression of an Mls-1a-like antigen that could be identified in mixed lymphocyte reaction in vitro, nor with the presence of Mtv-7, the endogenous mouse mammary tumor virus (MMTV) proviral loci. Spleen cells, bone marrow cells, and total thymocytes injected into newborn thymuses cannot induce V beta 6+ cell deletion. However, newborn thymuses grafted into old BALB/c mice behave like their recipients, suggesting that a new antigen, present in these old BALB/c mice, is indeed able to induce an Mls-1a-like clonal deletion. As other BALB/c colonies tested do not behave in same way, the hypothesis of a new exogenous deleting factor rather than a genetic transmission is likely. This may suggest that acquired clonal deletion is a more common phenomenon than expected, and may be the spontaneous reaction of the immune system to the introduction of a new retrovirus or other superantigen.

scholarly journals Clonal deletion induced by either radioresistant thymic host cells or lymphohemopoietic donor cells at different stages of class I-restricted T cell ontogeny.

1992 ◽  
Vol 175 (5) ◽  
pp. 1277-1283 ◽  
Author(s):  
D E Speiser ◽  
H Pircher ◽  
P S Ohashi ◽  
D Kyburz ◽  
H Hengartner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
Negative Selection ◽  
Host Cells ◽  
Thymic Epithelial Cells ◽  
Clonal Deletion ◽  
Mhc Molecules ◽  
Donor Cells ◽  
Self Antigens

Major histocompatibility complex (MHC) products and self-antigens expressed in the thymus determine the repertoire of mature alpha/beta T cells. While positive selection of self-MHC-restricted T cells is directed by MHC molecules expressed by thymic epithelial cells, negative selection depends to a large extent on self-antigens presented by lymphohemopoietic cells. However, radioresistant components of the thymus also influence negative selection, but it remains controversial whether this is accomplished by clonal deletion, clonal anergy, or other mechanisms. In this study, T cell development in mice expressing a transgenic T cell receptor (TCR) specific for lymphocytic choriomeningitis virus (LCMV) plus H-2Db was analyzed in the presence or absence of the viral antigen. A novel approach to analyze the thymic tissue requirements for negative selection was possible by comparing thymocyte selection in H-2Db versus H-2Dbm13 mice, since the latter allowed positive selection but not LCMV-specific deletion of transgenic TCR-expressing thymocytes. In irradiation bone marrow chimeras expressing the restriction element for negative selection (H-2Db) on host tissue, we show that radioresistant recipient cells in the thymus deleted developing T cells at an early stage of differentiation. In contrast, chimeras expressing H-2Db on lymphohemopoietic donor cells showed clonal deletion at a later stage during ontogeny.

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