Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine β-Thalassemia

E. Shuyu, Aman Seth, Peter Vogel, Matt Sommers, Taren Ong, Asha Pillai

Research output: Contribution to journalArticle

Abstract

Nonmyeloablative conditioning using total lymphoid irradiation (TLI) and rabbit antithymocyte serum (ATS) (the murine preclinical equivalent of antithymocyte globulin [ATG]) facilitates immune tolerance after bone marrow transplantation (BMT) across major histocompatibility complex (MHC) disparities and may be a useful strategy for nonmalignant disorders. We previously reported that donor effector T-cell function and graft-versus-host disease (GVHD) are regulated via recipient invariant natural killer T-cell (iNKT) interleukin-4-driven expansion of donor Foxp31 naturally occurring regulatory T cells (Tregs). This occurs via recipient iNKT-and STAT6-dependent expansion of recipient myeloid dendritic cells (MDCs) that induce contact-dependent expansion of donor Treg through PD-1/PD ligand signaling. After TLI/ATS1BMT,Gr-1lowCD11c1MDCs and Gr-1highCD11cneg myeloid-derived suppressor cells (MDSCs) were enriched in GVHD target organs. We now report that the recovery of both recipient MDSCs (P < .01) and MDCs (P < .01) is significantly increased when the alkylator cyclophosphamide (CTX) is added to TLI/ATS conditioning. In a BALB/c→B6 lethal GVHD model, adoptive transfer of MDSCs from TLI/ATS/CTX-conditioned recipients is associated with significantly improved GVHD colitis and survival (P < .001), conversion of MDSCs to PD ligand-expressing MDCs, and increased donor naturally occurring Treg recovery (P < .01) compared with control treatment. Using BALB/c donors and b-Thalassemic HW-80 recipients, we found significantly improved rates of engraftment and GVHD following TLI/ATS/CTX compared with TLI/ATS, lethal or sublethal total body irradiation/ATS/CTX, or CTX/ATS conditioning. These data provide preclinical support for trials of TLI/ATG/alkylator regimens for MHC-mismatched BMT for hemoglobinopathies. The data also delineate innate immune mechanisms by which TLI/ATS/CTX conditioning may augment transplantation tolerance.

Original languageEnglish (US)
Pages (from-to)3017-3030
Number of pages14
JournalBlood
Volume129
Issue number22
DOIs
StatePublished - Jun 1 2017

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Lymphatic Irradiation
Immune Tolerance
Thalassemia
Major Histocompatibility Complex
Bone Marrow Transplantation
Bone
Irradiation
Graft vs Host Disease
Grafts
T-cells
Serum
Myeloid Cells
Dendritic Cells
Natural Killer T-Cells
Antilymphocyte Serum
Alkylating Agents
Ligands
Transplantation Tolerance
Hemoglobinopathies
Adoptive Transfer

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine β-Thalassemia. / Shuyu, E.; Seth, Aman; Vogel, Peter; Sommers, Matt; Ong, Taren; Pillai, Asha.

In: Blood, Vol. 129, No. 22, 01.06.2017, p. 3017-3030.

Research output: Contribution to journalArticle

Shuyu, E. ; Seth, Aman ; Vogel, Peter ; Sommers, Matt ; Ong, Taren ; Pillai, Asha. / Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine β-Thalassemia. In: Blood. 2017 ; Vol. 129, No. 22. pp. 3017-3030.
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