The MHC molecule I-E is necessary but not sufficient for the clonal deletion of V beta 11-bearing T cells.

We have previously described a nonirradiation-based regimen combining costimulation blockade, busulfan, and donor bone marrow cells that promotes stable, high level chimerism, deletion of donor-reactive T cells, and indefinite survival of skin allografts in mice. The purpose of the current study is to determine the efficacy of this tolerance regimen in preventing acute and chronic rejection in a vascularized heart graft model and to compare this regimen with other putative tolerance protocols. Mice receiving costimulation blockade (CTLA4-Ig and anti-CD40 ligand) alone or in combination with donor cells enjoyed markedly prolonged heart graft survival and initially preserved histological structure. However, tolerance was not achieved, as evidenced by the eventual onset of chronic rejection characterized by obliterative vasculopathy and the rejection of secondary skin grafts. In contrast, following treatment with costimulation blockade, busulfan, and bone marrow, heart grafts survived indefinitely without detectable signs of chronic rejection or structural damage, even 100 days after placement of a secondary donor skin graft. We detected multilineage chimerism in peripheral blood, spleen, lymph nodes, and thymus, and peripheral deletion of donor-reactive cells was complete by day 90. These findings indicate that only the CD40/CD28 blockade chimerism induction regimen prevents both acute and chronic rejection of vascularized organ transplants. Further testing of these strategies in a preclinical large animal model is warranted.

Section: Effect On Recipient Immune System: Sustained Deletion Of V␤1mentioning

confidence: 99%

Prevention of Chronic Rejection in Murine Cardiac Allografts: A Comparison of Chimerism- and Nonchimerism-Inducing Costimulation Blockade-Based Tolerance Induction Regimens

Shirasugi

Adams

Durham

et al. 2002

“…The donor strain B10.BR mice express I-E, resulting in the deletion of V␤5.1/2 ϩ and V␤11 ϩ T cells (18,19). As B10 mice do not express I-E, they do not delete these two V␤ subfamilies (19,20). Relative expression indicates the percentage of V␤-positive cells within the CD8 ϩ or CD4 ϩ T cell subsets of the host (H2K b ) lymphoid gate in peripheral blood.…”

Section: Production Of Donor T Cells Is Critical For Clonal Deletion mentioning

confidence: 99%

Production of Donor T Cells Is Critical for Induction of Donor-Specific Tolerance and Maintenance of Chimerism

Chilton

Huang

et al. 2004

Nonmyeloablative conditioning has significantly reduced the morbidity associated with bone marrow transplantation. The donor hemopoietic cell lineage(s) responsible for the induction and maintenance of tolerance in nonmyeloablatively conditioned recipients is not defined. In the present studies we evaluated which hemopoietic stem cell-derived components are critical to the induction of tolerance in a total body irradiation-based model. Recipient B10 mice were pretreated with mAbs and transplanted with allogeneic B10.BR bone marrow after conditioning with 100–300 cGy total body irradiation. The proportion of recipients engrafting increased in a dose-dependent fashion. All chimeric recipients exhibited multilineage donor cell production. However, induction of tolerance correlated strictly with early production of donor T cells. The chimeras without donor T cells rejected donor skin grafts and demonstrated strong antidonor reactivity in vitro, while possessing high levels of donor chimerism. These animals lost chimerism within 8 mo. Differentiation into T cells was aborted at a prethymic stage in recipients that did not produce donor T cells. Moreover, donor Ag-driven clonal deletion of recipient T cells occurred only in chimeras with donor T cells. These results demonstrate that donor T cell production is critical in the induction of transplantation tolerance and the maintenance of durable chimerism. In addition, donor T cell production directly correlates with the deletion of potentially alloreactive cells.

“…The donor strain B10.A expresses I-E, which is required to present superantigens derived from mammary tumor virus 8 and 9 endogenous retroviruses encoded in the B6/B10 background genome (18 -20). Developing thymocytes whose TCR contain V␤5 and V␤11 subunits, which bind to these superantigens, are deleted in I-E-positive B10.A mice, but not in B6 mice, because they do not express I-E (19,21). The mice that received low-dose TCD mAbs plus MR1 showed profound reductions in the percentage of V␤5 ϩ CD4 PBL (normal B6, 2.56%; normal B10.A, 0.00%) to 0.18 Ϯ 0.13%, and V␤11 ϩ CD4 PBL (normal B6, 5.07%; normal B10.A, 0.00%) to 0.17 Ϯ 0.14% at 8 wk post-BMT.…”

Section: Incompletely Depleting Doses Of Anti-cd4 and Anti-cd8 Mabs Omentioning

confidence: 99%

CD4 T Cell-Mediated Alloresistance to Fully MHC-Mismatched Allogeneic Bone Marrow Engraftment Is Dependent on CD40-CD40 Ligand Interactions, and Lasting T Cell Tolerance Is Induced by Bone Marrow Transplantation with Initial Blockade of this Pathway

Ito

Kurtz

Shaffer

et al. 2001

108

129

Costimulatory blockade can be used to promote allogeneic marrow engraftment and tolerance induction, but on its own is not 100% reliable. We sought to determine whether one or the other of the CD4 or CD8 T cell subsets of the recipient was primarily responsible for resistance to allogeneic marrow engraftment in mice receiving costimulatory blockade, and to use this information to develop a more reliable, minimal conditioning regimen for induction of mixed chimerism and transplantation tolerance. We demonstrate that a single anti-CD40 ligand mAb treatment is sufficient to completely overcome CD4 cell-mediated resistance to allogeneic marrow engraftment and rapidly induce CD4 cell tolerance, but does not reliably overcome CD8 CTL-mediated alloresistance. The data suggest that costimulation, which activates alloreactive CTL, is insufficient to activate alloreactive CD4 cells when the CD40 pathway is blocked. The addition of host CD8 T cell depletion to anti-CD40 ligand treatment reliably allows the induction of mixed chimerism and donor-specific skin graft tolerance in 3 Gy-irradiated mice receiving fully MHC-mismatched bone marrow grafts. Thus, despite the existence of multiple costimulatory pathways and pathways of APC activation, our studies demonstrate an absolute dependence on CD40-mediated events for CD4 cell-mediated rejection of allogeneic marrow. Exposure to donor bone marrow allows rapid tolerization of alloreactive CD4 cells when the CD40 pathway is blocked, leading to permanent marrow engraftment and intrathymic tolerization of T cells that develop subsequently.