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After iNature allogeneic hematopoietic cell transplantation (HCT), acute graft-versus-host disease (aGVHD) is mediated by alloreactive donor CD4 + and CD8 + T cells.
The gastrointestinal tract is the main target of aGVHD, and the severity of intestinal damage (intestine) determines the result of aGVHD.
On February 5, 2021, Chen Yuanzhong of Fujian Medical University and Zeng Defu of the Beckman Institute of the City of Hope in the United States published an online communication titled "IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-" in Nature Communications.
versus-host disease in mice" research paper, which shows that the pathogenesis of SR-Gut-aGVHD is related to the reduction of IFN-γ+ Th / Tc1 cells and the preferential expansion of IL-17-IL-22 + Th / Tc22 cells related.
IL-22 of Th/Tc22 cells causes dysbiosis of cell composition in a Reg3γ-dependent manner.
In the absence of CD4 + T cells, transplantation of IFN-γ deficient donor CD8 + T cells can produce the phenotype of SR-Gut-aGVHD.
The lack of IFN-γ in the donor CD8 + T cells also leads to the PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNPs), which also increases the expansion of Tc22 cells.
Support dual regulation, simultaneous pathogen induction and CX3CR1hi MNP depletion, can produce complete Gut-aGVHD.
Therefore, the results of this study provide insights into the pathogenesis of SR-Gut-aGVHD and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in the treatment of SR-Gut-aGVHD.
After allogeneic hematopoietic cell transplantation (HCT), acute graft-versus-host disease (aGVHD) is mediated by alloreactive donor CD4 + and CD8 + T cells.
The gastrointestinal tract is the main target of aGVHD, and the severity of intestinal damage (intestine) determines the result of aGVHD.
IFN-γ+ Th1/Tc1 cells play a major role in destroying intestinal Paneth cells.
The latter produces Reg3γ, which has bactericidal activity against Gram-positive bacteria and maintains the steady state of the intestinal microbiome.
The aGVHD damage of intestinal epithelial cells and Paneth cells leads to dysbiosis of cell composition and aggravates aGVHD.
Under inflammatory conditions, the increased production of IL-22 and Reg3γ in intestinal tissues can also cause dysbiosis of cell composition and colonization of pathogenic bacteria.
IL-22 in intestinal tissues can be produced by innate lymphocytes, NK and NKT cells, and Th17 and Th22 cells.
Th/Tc17 cells include IL-17A + IL-22- and IL-17A + IL-22 + subsets, and their differentiation is regulated by RORα and RORc (RORγt).
Th/Tc22 differentiation is regulated by AHR.
In Th22 cells, RORγt enhances AHR expression, and T-bet17 inhibits AHR expression.
In healthy individuals, CX3CR1+ intestinal mononuclear phagocytes (MNP) play an important role in removing intestinal invasive pathogens and preventing the transfer of pathogens from the intestinal lumen to the mesenteric lymph nodes (MLN) and liver.
CX3CR1 + MNP also promotes epithelial barrier repair and regulates Th17 and Treg differentiation.
Hematopoietic cells from sources including CX3CR1 + MNP are the targets of aGVHD.
It is not yet known how the donor-derived CX3CR1 + MNP cells regulate Gut-aGVHD.
Corticosteroids are used for the initial treatment of aGVHD.
Some patients develop steroid-resistant or refractory (SR) Gut-aGVHD.
The pathogenesis of SR-Gut-aGVHD remains a mystery.
Steroid therapy can effectively inhibit Th1/Tc1, but not Th17, and IL-17A + CD4 + T cells will infiltrate the intestinal tissue of patients with SR-Gut-aGVHD30.
However, the use of ATG or anti-CD25-targeted steroid-resistant T cells in SR-Gut-aGVHD patients is still ineffective.
Other studies have shown that although IL-22 from host-type innate lymphocytes enhances the survival of intestinal epithelial stem cells and reduces Gut-aGVHD, IL-22 from donor T cells enhances Gut-aGVHD.
The study observed that steroid treatment can reduce IFN-γ+ Th1/Tc1, but preferentially increase the expansion of Th/Tc22 cells.
IL-22 in Th/Tc22 cells causes dysbiosis of cell composition.
Lack of IFN-γ can lead to depletion of protective donor CX3CR1hi MNP cells in the intestinal tissue; IL-22 induces pathogens and depletes CX3CR1hi MNP cells at the same time, which can lead to SR-Gut-aGVHD.
This research provides insights into the pathogenesis of SR-Gut-aGVHD and opens the way for the development of methods to prevent and treat SR-Gut-aGVHD.
Reference message: https://
The gastrointestinal tract is the main target of aGVHD, and the severity of intestinal damage (intestine) determines the result of aGVHD.
On February 5, 2021, Chen Yuanzhong of Fujian Medical University and Zeng Defu of the Beckman Institute of the City of Hope in the United States published an online communication titled "IL-22-dependent dysbiosis and mononuclear phagocyte depletion contribute to steroid-resistant gut graft-" in Nature Communications.
versus-host disease in mice" research paper, which shows that the pathogenesis of SR-Gut-aGVHD is related to the reduction of IFN-γ+ Th / Tc1 cells and the preferential expansion of IL-17-IL-22 + Th / Tc22 cells related.
IL-22 of Th/Tc22 cells causes dysbiosis of cell composition in a Reg3γ-dependent manner.
In the absence of CD4 + T cells, transplantation of IFN-γ deficient donor CD8 + T cells can produce the phenotype of SR-Gut-aGVHD.
The lack of IFN-γ in the donor CD8 + T cells also leads to the PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNPs), which also increases the expansion of Tc22 cells.
Support dual regulation, simultaneous pathogen induction and CX3CR1hi MNP depletion, can produce complete Gut-aGVHD.
Therefore, the results of this study provide insights into the pathogenesis of SR-Gut-aGVHD and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in the treatment of SR-Gut-aGVHD.
After allogeneic hematopoietic cell transplantation (HCT), acute graft-versus-host disease (aGVHD) is mediated by alloreactive donor CD4 + and CD8 + T cells.
The gastrointestinal tract is the main target of aGVHD, and the severity of intestinal damage (intestine) determines the result of aGVHD.
IFN-γ+ Th1/Tc1 cells play a major role in destroying intestinal Paneth cells.
The latter produces Reg3γ, which has bactericidal activity against Gram-positive bacteria and maintains the steady state of the intestinal microbiome.
The aGVHD damage of intestinal epithelial cells and Paneth cells leads to dysbiosis of cell composition and aggravates aGVHD.
Under inflammatory conditions, the increased production of IL-22 and Reg3γ in intestinal tissues can also cause dysbiosis of cell composition and colonization of pathogenic bacteria.
IL-22 in intestinal tissues can be produced by innate lymphocytes, NK and NKT cells, and Th17 and Th22 cells.
Th/Tc17 cells include IL-17A + IL-22- and IL-17A + IL-22 + subsets, and their differentiation is regulated by RORα and RORc (RORγt).
Th/Tc22 differentiation is regulated by AHR.
In Th22 cells, RORγt enhances AHR expression, and T-bet17 inhibits AHR expression.
In healthy individuals, CX3CR1+ intestinal mononuclear phagocytes (MNP) play an important role in removing intestinal invasive pathogens and preventing the transfer of pathogens from the intestinal lumen to the mesenteric lymph nodes (MLN) and liver.
CX3CR1 + MNP also promotes epithelial barrier repair and regulates Th17 and Treg differentiation.
Hematopoietic cells from sources including CX3CR1 + MNP are the targets of aGVHD.
It is not yet known how the donor-derived CX3CR1 + MNP cells regulate Gut-aGVHD.
Corticosteroids are used for the initial treatment of aGVHD.
Some patients develop steroid-resistant or refractory (SR) Gut-aGVHD.
The pathogenesis of SR-Gut-aGVHD remains a mystery.
Steroid therapy can effectively inhibit Th1/Tc1, but not Th17, and IL-17A + CD4 + T cells will infiltrate the intestinal tissue of patients with SR-Gut-aGVHD30.
However, the use of ATG or anti-CD25-targeted steroid-resistant T cells in SR-Gut-aGVHD patients is still ineffective.
Other studies have shown that although IL-22 from host-type innate lymphocytes enhances the survival of intestinal epithelial stem cells and reduces Gut-aGVHD, IL-22 from donor T cells enhances Gut-aGVHD.
The study observed that steroid treatment can reduce IFN-γ+ Th1/Tc1, but preferentially increase the expansion of Th/Tc22 cells.
IL-22 in Th/Tc22 cells causes dysbiosis of cell composition.
Lack of IFN-γ can lead to depletion of protective donor CX3CR1hi MNP cells in the intestinal tissue; IL-22 induces pathogens and depletes CX3CR1hi MNP cells at the same time, which can lead to SR-Gut-aGVHD.
This research provides insights into the pathogenesis of SR-Gut-aGVHD and opens the way for the development of methods to prevent and treat SR-Gut-aGVHD.
Reference message: https://
