IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

Pan, Bin; Wang, Dong; Li, Lingling; Shang, Longmei; Xia, Fan; Zhang, Fan; Zhang, Ying; Gale, Robert Peter; Xu, Min; Li, Zhenyu; Xu, Kailin

doi:10.1016/j.bbmt.2019.06.002

Cited by 25 publications

(22 citation statements)

References 42 publications

(52 reference statements)

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“…When tested in preclinical models of acute GVHD, treatment with recombinant IL-22 generally improved the disease, increased numbers of Lgr5 + stem cells, enhanced expression of antimicrobial peptides Reg3α and Reg3γ, and improved epithelial integrity (Lindemans et al, 2015; Zhao et al, 2018). The beneficial effect of IL-22 is not limited to the intestine, as IL-22 is also critical for the regeneration and survival of thymic epithelial cells (Dudakov et al, 2017; Pan et al, 2019). IL-22 derived from thymic resident ILC3 supports thymus regeneration during allogeneic transplantation (Dudakov et al, 2012, 2017).…”

Section: Gvhdmentioning

confidence: 99%

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The role of IL-22 in intestinal health and disease

Keir¹,

Yi²,

Lu³

et al. 2020

Journal of Experimental Medicine

244

160

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The cytokine interleukin-22 (IL-22) is a critical regulator of epithelial homeostasis. It has been implicated in multiple aspects of epithelial barrier function, including regulation of epithelial cell growth and permeability, production of mucus and antimicrobial proteins (AMPs), and complement production. In this review, we focus specifically on the role of IL-22 in the intestinal epithelium. We summarize recent advances in our understanding of how IL-22 regulates homeostasis and host defense, and we discuss the IL-22 pathway as a therapeutic target in diseases of the intestine, including inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), and cancer.

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Section: Gvhdmentioning

confidence: 99%

“…Accordingly, lack of recipient IL-22 leads to a reduced number of thymic epithelial cells and subsequent expression of genes related to thymic negative selection (e.g., Foxn1 , Aire ). This effect of IL-22 may exacerbate GVHD through defective negative selection of autoreactive T cells (Dudakov et al, 2017; Pan et al, 2019).…”

Section: Gvhdmentioning

confidence: 99%

The role of IL-22 in intestinal health and disease

Keir¹,

Yi²,

Lu³

et al. 2020

Journal of Experimental Medicine

244

160

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“…The first of these was centered around the production of Interleukin-22 (IL-22), a member of the IL-10 family that typically targets non-hematopoietic cells such as epithelial cells and fibroblasts (73). In this regenerative network, acute damage to the thymus (and specifically the depletion of thymocytes) triggers the release of Interleukin-23 (IL-23) from dendritic cells, which induces the production of IL-22 by a group 3 innate lymphoid cells (2,(74)(75)(76). Expression of IL-22R in the thymus is lacking on thymocytes but detected in both cTECs and mTECs populations (2).…”

Section: Interleukin-22mentioning

confidence: 99%

When the Damage Is Done: Injury and Repair in Thymus Function

Kinsella

Dudakov

2020

Front. Immunol.

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Even though the thymus is exquisitely sensitive to acute insults like infection, shock, or common cancer therapies such as cytoreductive chemo-or radiation-therapy, it also has a remarkable capacity for repair. This phenomenon of endogenous thymic regeneration has been known for longer even than its primary function to generate T cells, however, the underlying mechanisms controlling the process have been largely unstudied. Although there is likely continual thymic involution and regeneration in response to stress and infection in otherwise healthy people, acute and profound thymic damage such as that caused by common cancer cytoreductive therapies or the conditioning regimes as part of hematopoietic cell transplantation (HCT), leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse. Furthermore, this capacity for regeneration declines with age as a function of thymic involution; which even at steady state leads to reduced capacity to respond to new pathogens, vaccines, and immunotherapy. Consequently, there is a real clinical need for strategies that can boost thymic function and enhance T cell immunity. One approach to the development of such therapies is to exploit the processes of endogenous thymic regeneration into novel pharmacologic strategies to boost T cell reconstitution in clinical settings of immune depletion such as HCT. In this review, we will highlight recent work that has revealed the mechanisms by which the thymus is capable of repairing itself and how this knowledge is being used to develop novel therapies to boost immune function.

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“…Bone marrow transplants were performed as described 13 . BALB/c mice were treated by 7.5 Gy total body irradiation and received an infusion of 5 × 10 6 T cell–depleted bone marrow (TCD‐BM) cells from C57BL/6 donors 24 hours later.…”

Section: Methodsmentioning

confidence: 99%

“…To detect expression of mRNA levels, qPCR was performed as described 13 . The following primers were used: Tbx21 (ACTAAGCAAGGACGGCGAAT and TAATGGCTTGTGGGCTCCAG), Prdm1 (CACAGAAAACGTGCCACAGG and TAGACTTGGGGGCAGCCTTG), Nfatc1 (GCTCCTGCTCCTCCTCCT and ACTGTAGTGTTCTTCCTCGGC), Fos (TTTCAACGCCGACTACGAGG and TCTGCGCAAAAGTCCTGTGT), Foxo1 (ATGTGTTGCCCAACCAAAGC and ATGTAGCCTGCTCACTAACTCTT), Irf9 (GGGGTATGGTAAGGAGAAGGATG and AAATGGCCACTCTCCACCTG), Notch1 (ACAGTGCAACCCCCTGTATG and AGTTGTTCCGTAGCTGGTCG), and Gapdh (TTGATGGCAACAATCTCCAC and CGTCCCGTAGACAAAATGGT).…”

Section: Methodsmentioning

confidence: 99%

PD-1 antibody and ruxolitinib enhances graft-versus-lymphoma effect without increasing acute graft-versus-host disease in mice

Pan

Shang

Liu

et al. 2021

American Journal of Transplantation

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Boosting T cell immune response posttransplant with checkpoint inhibitors increases graft‐versus‐lymphoma (GVL) effects at the cost of increasing acute graft‐versus‐host disease (aGVHD). A combined targeted therapy is needed to decrease checkpoint inhibitors‐induced aGVHD without impairing GVL. We studied whether this competition could be avoided by giving concurrent anti‐PD‐1 antibody and ruxolitinib in allotransplant mouse models in which recipients were challenged with A20 or EL4 lymphoma cells. Given alone the PD‐1 antibody increased GVL but did not improve survival of recipients challenged with A20 cells because of increased deaths from aGVHD. Adding ruxolitinib decreased levels of effector T cells and related cytokines. Tbx21‐ T cells had higher PD‐1 levels compared with Tbx21+ T cells. Ruxolitinib increased PD‐1 levels on donor T cells by suppressing Tbx21 expression. Ruxolitinib increased apoptosis of T cells which was reversed by the PD‐1 antibody. PD‐1 antibody preserved expression of granzyme B and cytotoxicity of T cells which were decreased by ruxolitinib. The net result of combined therapy was increased GVL, no increase in aGVHD and increased survival. The combined therapy improved survival of recipients challenged by A20 cells which expressed high level of PD‐L1, but not EL4 cells which do not express PD‐L1.

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IL-22 Accelerates Thymus Regeneration via Stat3/Mcl-1 and Decreases Chronic Graft-versus-Host Disease in Mice after Allotransplants

Cited by 25 publications

References 42 publications

The role of IL-22 in intestinal health and disease

The role of IL-22 in intestinal health and disease

When the Damage Is Done: Injury and Repair in Thymus Function

PD-1 antibody and ruxolitinib enhances graft-versus-lymphoma effect without increasing acute graft-versus-host disease in mice

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