Dataset Information

Expansion of CD45RA^-FOXP3⁺⁺ regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation.

ABSTRACT:

Objectives

Simultaneous transplantation of a solid organ and bone marrow from the same donor is a possible means of achieving transplant tolerance. Here, we attempted to identify biomarkers that indicate transplant tolerance for discontinuation of immunosuppressants in combined kidney and bone marrow transplantation (CKBMT).

Methods

Conventional kidney transplant (KT) recipients (n = 20) and CKBMT recipients (n = 6) were included in this study. We examined various immunological parameters by flow cytometry using peripheral blood mononuclear cells (PBMCs), including the frequency and phenotype of regulatory T (Treg) cell subpopulations. We also examined the suppressive activity of the Treg cell population in the setting of mixed lymphocyte reaction (MLR) with or without Treg cell depletion.

Results

Among six CKBMT recipients, three successfully discontinued immunosuppressants (tolerant group) and three could not (non-tolerant group). The CD45RA^-FOXP3⁺⁺ Treg cell subpopulation was expanded in CKBMT recipients compared to conventional kidney transplant patients, and this was more obvious in the tolerant group than the non-tolerant group. In addition, high suppressive activity of the Treg cell population was observed in the tolerant group. The ratio of CD45RA^-FOXP3⁺⁺ Treg cells to CD45RA^-FOXP3⁺ cells indicated good discrimination between the tolerant and non-tolerant groups.

Conclusion

Thus, our findings propose a biomarker that can distinguish CKBMT patients who achieve transplant tolerance and are eligible for discontinuation of immunosuppressants and may provide insight into tolerance mechanisms in CKBMT.

SUBMITTER: Kwon Y

PROVIDER: S-EPMC8353318 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Expansion of CD45RA<sup>-</sup>FOXP3<sup>++</sup> regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation.

Kwon Yeongbeen Y Lee Kyo Won KW Kim You Min YM Park Hyojun H Jung Min Kyung MK Choi Young Joon YJ Son Jin Kyung JK Hong JuHee J Park Su-Hyung SH Kwon Ghee Young GY Yoo Heejin H Kim Kyunga K Kim Sung Joo SJ Park Jae Berm JB Shin Eui-Cheol EC

Clinical & translational immunology 20210809 8

<h4>Objectives</h4>Simultaneous transplantation of a solid organ and bone marrow from the same donor is a possible means of achieving transplant tolerance. Here, we attempted to identify biomarkers that indicate transplant tolerance for discontinuation of immunosuppressants in combined kidney and bone marrow transplantation (CKBMT).<h4>Methods</h4>Conventional kidney transplant (KT) recipients (<i>n</i> = 20) and CKBMT recipients (<i>n</i> = 6) were included in this study. We examined various im ...[more]

PMID: 34401148

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Project description:We showed previously that nonmyeloablative total lymphoid irradiation/rabbit anti-thymocyte serum (TLI/ATS) conditioning facilitates potent donor-recipient immune tolerance following bone marrow transplantation (BMT) across MHC barriers via recipient invariant NKT (iNKT) cell-derived IL-4-dependent expansion of donor Foxp3(+) naturally occurring regulatory T cells (nTregs). In this study, we report a more specific mechanism. Wild-type (WT) BALB/c (H-2(d)) hosts were administered TLI/ATS and BMT from WT or STAT6(-/-) C57BL/6 (H-2(b)) donors. Following STAT6(-/-) BMT, donor nTregs demonstrated no loss of proliferation in vivo, indicating that an IL-4-responsive population in the recipient, rather than the donor, drives donor nTreg proliferation. In graft-versus-host disease (GVHD) target organs, three recipient CD11b(+) cell subsets (Gr-1(high)CD11c(-), Gr-1(int)CD11c(-), and Gr-1(low)CD11c(+)) were enriched early after TLI/ATS + BMT versus total body irradiation/ATS + BMT. Gr-1(low)CD11c(+) cells induced potent H-2K(b+)CD4(+)Foxp3(+) nTreg proliferation in vitro in 72-h MLRs. Gr-1(low)CD11c(+) cells were reduced significantly in STAT6(-/-) and iNKT cell-deficient Jα18(-/-) BALB/c recipients after TLI/ATS + BMT. Depletion of CD11b(+) cells resulted in severe acute GVHD, and adoptive transfer of WT Gr-1(low)CD11c(+) cells to Jα18(-/-) BALB/c recipients of TLI/ATS + BMT restored day-6 donor Foxp3(+) nTreg proliferation and protection from CD8 effector T cell-mediated GVHD. Blockade of programmed death ligand 1 and 2, but not CD40, TGF-β signaling, arginase 1, or iNOS, inhibited nTreg proliferation in cocultures of recipient-derived Gr-1(low)CD11c(+) cells with donor nTregs. Through iNKT-dependent Th2 polarization, myeloid-derived immunomodulatory dendritic cells are expanded after nonmyeloablative TLI/ATS conditioning and allogeneic BMT, induce PD-1 ligand-dependent donor nTreg proliferation, and maintain potent graft-versus-host immune tolerance.

Dataset Information

Expansion of CD45RA^-FOXP3⁺⁺ regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation.

Objectives

Methods

Results

Conclusion

Publications

Expansion of CD45RA<sup>-</sup>FOXP3<sup>++</sup> regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Expansion of CD45RA-FOXP3++ regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation.

Objectives

Methods

Results

Conclusion

Publications

Expansion of CD45RA<sup>-</sup>FOXP3<sup>++</sup> regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Expansion of CD45RA^-FOXP3⁺⁺ regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation.