MHC-mismatched mixed chimerism augments thymic regulatory T-cell production and prevents relapse of EAE in mice

Wu, Limin; Li, Nainong; Zhang, Mingfeng; Xue, Sheng‐Li; Cassady, Kaniel; Lin, Qi; Riggs, Arthur D.; Zeng, Defu

doi:10.1073/pnas.1521157112

Cited by 14 publications

(15 citation statements)

References 37 publications

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“…After peripheral T cells were activated, only a small number of lymphocytes crossed the BBB and in ltrated the CNS, causing mild neurological de cit. With the enhanced permeability of the BBB, the CNS was invaded by millions of pro-in ammatory lymphocytes and macrophages in the second wave within hours, which was consistent with the clinical manifestations of MS, further suggesting that T cell migration plays a central role in the pathogenesis of MS [24,25]. In recent years, attention has been given to the migration of CD8 + T cells into the CNS during this process.…”

Section: Eae Is Mediated By the Imbalance Of Lymphocytesmentioning

confidence: 77%

2-BFI Attenuates Experimental Autoimmune Encephalomyelitis in Mice via Regulation of Lymphocytes Subsets

Shang

Wang

Xi³

et al. 2020

Preprint

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Background: Imidazoline compounds are well accepted to exhibit various pharmacological effects including antidepressant, anti-inflammatory, analgesic, anti-morphine tolerance and inhibit the activity of monoamine oxidase. 2-(-2-benzofuranyl)-2-imidazoline (2-BFI), a selective imidazoline 2 receptor (I2R) ligand, has been proven to exhibit therapeutic effects for various neuroimmunological diseases. However, the mechanism behind its neuroprotective properties remains elusive. Methods: In this study, we used 2-BFI for the treatment of mice with experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG33-55). The clinical signs of neurological deficits were evaluated daily. The demyelination and inflammatory infiltration in the CNS of mice with EAE were examined by Luxol Fast Blue (LFB) staining and hematoxylin-eosin (H&E) staining. Flow cytometry was utilized to examine the ratios of lymphocyte subsets in the periphery and CNS of mice with EAE. We also used Reverse Transcription–Polymerase Chain Reaction (RT-PCR) to observe the changes of expression of inflammatory cytokines by 2-BFI intervention. Results: We found that 2-BFI significantly reduced the incidence of EAE and attenuated the severity of neurological disability. Pathological staining showed that the infiltration of inflammatory cells and demyelination in the central nervous system (CNS) of the mice were markedly alleviated via 2-BFI intervention. To explore the mechanism of action of 2-BFI, we used flow cytometry to determine immunophenotypes in the spleen and CNS of the mice. We discovered that 2-BFI significantly decreased the ratio of CD28+ lymphocytes and B cells in the spleen of EAE mice. In the CNS, the expression of CD4+ T cells was downregulated by 2-BFI, while B cells and CD39+ lymphocytes were dramatically increased. RT-PCR also demonstrated that the level of IFN-γ mRNA secreted by CD4+T cells was lower than that in the CNS of EAE mice, while the levels of TGF- β and IL-10mRNA secreted by Treg and B cells were increased with 2-BFI intervention. Conclusion: 2-BFI could ameliorate EAE-induced neurobehavioral deficits and reduce the infiltration of inflammatory cells via regulating the activation and migration of lymphocyte subsets. This study provides a new explanation for the protective mechanism of 2-BFI in neuroimmune diseases.

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Section: Eae Is Mediated By the Imbalance Of Lymphocytesmentioning

confidence: 77%

2-BFI Attenuates Experimental Autoimmune Encephalomyelitis in Mice via Regulation of Lymphocytes Subsets

Shang

Wang

Xi³

et al. 2020

Preprint

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“…Haplo-MC was induced through a clinically applicable conditioning regimen of ATG + CY + PT and infusion of CD4 + T cell-depleted spleen (CD4 − -SPL) and bone marrow (BM) from haploidentical (H-2 g7/s ) F1 donors, as described in our previous publications ( 16 , 20 ). The firmly established diabetic NOD mice developed stable Haplo-MC with both donor- and host-type T, B, and myeloid cells in the peripheral blood, spleen, BM, and thymus ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Induction of haploidentical mixed chimerism (Haplo-MC) represents a curative approach for autoimmunity in firmly established diabetic T1D mice ( 16 ). Haploidentical HCT (Haplo-HCT) has been widely used for treating nonmalignant hematological disorders ( 17 ), and induction of Haplo-MC prevents the side effect of graft versus host disease (GVHD) ( 4 , 8 , 16 , 18 – 20 ). GVHD is often associated with complete chimerism in classical HCT for treating malignant hematological diseases ( 21 ).…”

mentioning

confidence: 99%

“…We have developed a radiation-free conditioning regimen for induction of Haplo-MC in mouse models, in which recipients are first conditioned with antithymocyte globulin (ATG) and a low-dose of cyclophosphamide (CY) and pentostatin (PT), and then transplanted with CD4 + T cell-depleted hematopoietic graft ( 16 , 20 ). This regimen shows minimal toxicity in mice and is now under phase I safety clinical trial enrolling patients with sickle cell disease ( 56 ).…”

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confidence: 99%

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Reversal of autoimmunity by mixed chimerism enables reactivation of β cells and transdifferentiation of α cells in diabetic NOD mice

Tang

Zhang

Zeng

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9+ ductal progenitors, Nestin+ mesenchymal stem cells, and glucagon-producing α cells, we have found that both reactivation of dysfunctional low-level insulin expression (insulinlo) β cells and neogenesis contribute to the regeneration, with the latter predominantly coming from transdifferentiation of α cells. These results indicate that, after reversal of autoimmunity, reactivation of β cells and transdifferentiation of α cells can provide sufficient new functional β cells to reach euglycemia in firmly established T1D.

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“…The increased thymic production of C57BL/6 (H2-A b ) donor-type tTreg cells may result from positive selection of donor-type Treg cells by the H2-A g7 –donor antigen complex on host-type DCs in the thymic medullary. We observed a markedly increased percentage of tTreg cells among CD4 + CD8 + (DP) and CD4 + CD8 − (SP) thymocytes in the thymus of MHC-mismatched mixed chimeric NOD (H2-A g7 ) mice but not in the MHC-mismatched mixed chimeric SJL/J (H2-A S ) mice ( 73 ), suggesting that host expression of H2-A g7 plays an important role. In addition, the percentage of donor-type tTreg cells was also significantly increased in MHC-matched mixed chimeric NOD mice given transplants from congenic H2-A g7 C57BL/6 mice, although it was less than in the MHC-mismatched mixed chimeras, suggesting that H2-A g7 presenting minor antigens from C57BL/6 donors also play an important role.…”

Section: Discussionmentioning

confidence: 96%

MHC-mismatched mixed chimerism restores peripheral tolerance of noncross-reactive autoreactive T cells in NOD mice

Zhang

Racine

Lin

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceMixed chimerism has shown good potential to cure some autoimmune diseases and prevent tissue rejection. It is known that MHC-mismatched but not -matched mixed chimerism effectively tolerizes autoreactive T cells, even those noncross-reactive T cells that do not directly recognize donor-type antigen presenting cells [i.e., dendritic cells (DCs)]. How this is accomplished remains unknown. These studies have shown that tolerizing peripheral residual host-type noncross-reactive autoreactive T cells requires engraftment of donor-type DCs and involves a host-type DC-mediated increase in donor-type Treg cells, which associates with restoration of tolerogenic features of host-type plasmacytoid DCs and expansion of host-type Treg cells. This study suggests a previously unrecognized tolerance network among donor- and host-type DCs and Treg cells in MHC-mismatched mixed chimeras.

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MHC-mismatched mixed chimerism augments thymic regulatory T-cell production and prevents relapse of EAE in mice

Cited by 14 publications

References 37 publications

2-BFI Attenuates Experimental Autoimmune Encephalomyelitis in Mice via Regulation of Lymphocytes Subsets

2-BFI Attenuates Experimental Autoimmune Encephalomyelitis in Mice via Regulation of Lymphocytes Subsets

Reversal of autoimmunity by mixed chimerism enables reactivation of β cells and transdifferentiation of α cells in diabetic NOD mice

MHC-mismatched mixed chimerism restores peripheral tolerance of noncross-reactive autoreactive T cells in NOD mice

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