GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

Hess, Nicholas J; Brown, Matthew E.; Capitini, Christian M.

doi:10.3389/fimmu.2021.723544

Cited by 32 publications

(33 citation statements)

References 138 publications

(261 reference statements)

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“…In the group of allogeneic HCT recipients, a specific posttransplant complication, graft-versus-host disease, needs to be addressed. Since a dysregulation of immune mechanisms is responsible for the pathogenesis of this condition [ 38 ], the safety of COVID vaccination in transplant patients has been called into question. In our experience, vaccinations did not affect the occurrence and clinical course of GvHD.…”

Section: Discussionmentioning

confidence: 99%

Two Doses of BNT162b2 mRNA Vaccine in Patients after Hematopoietic Stem Cell Transplantation: Humoral Response and Serological Conversion Predictors

Majcherek

Matkowska-Kocjan

Szymczak

et al. 2022

Cancers

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Vaccination against SARS-CoV-2 is currently the best tool in the fight against the COVID-19 pandemic. However, there are limited data on its efficacy and safety after hematopoietic stem cell transplantation (HCT). We present the results of a prospective analysis of the humoral response to two doses of BNT162b2 mRNA vaccine in 93 adult patients, including 29 after autologous HCT (autoHCT) and 64 after allogeneic HCT (alloHCT). Positive anti-SARS-CoV-2 antibodies were detected before vaccination in 25% of patients despite a negative medical history of COVID-19. Seroconversion after vaccination was achieved in 89% of patients after alloHCT and in 96% after autoHCT, without grade 3/4 adverse events. Post-vaccination anti-SARS-CoV-2 antibody level correlated with the time from transplant and absolute B-cell count at the vaccination. In univariate analysis restricted to the alloHCT group, short time since transplantation, low B-cell count, low intensity conditioning, GvHD, and immunosuppressive treatment at the vaccination were associated with lack of seroconversion. In the multivariate model, the only negative predictor of seroconversion remained treatment with calcineurin inhibitor (CNI). In conclusion, the BNT162b2 mRNA vaccine is highly immunogenic in patients after HCT, but treatment with CNI at the time of vaccination has a strong negative impact on the humoral response

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Section: Discussionmentioning

confidence: 99%

Two Doses of BNT162b2 mRNA Vaccine in Patients after Hematopoietic Stem Cell Transplantation: Humoral Response and Serological Conversion Predictors

Majcherek

Matkowska-Kocjan

Szymczak

et al. 2022

Cancers

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“…While CB17/Icr-Prkdc scid /CrlCrlj mice lack functional lymphocytes, they do have normal natural killer cells, macrophages, and granulocytes [59], which could attack the donor cells and the injected human MSCs, thereby limiting their lifespan. Additionally, mice and humans have been found to have differing immunology and GvHD pathology [60,61]. In humans, GvHD pathology was found to be globally affected by all immune cells.…”

Section: Discussionmentioning

confidence: 99%

IL-10 mRNA Engineered MSCs Demonstrate Enhanced Anti-Inflammation in an Acute GvHD Model

Zhang

Delawary

Huang

et al. 2021

Cells

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Mesenchymal stem cells (MSCs) are used in various studies to induce immunomodulatory effects in clinical conditions associated with immune dysregulation such as graft versus host disease (GvHD). However, most of these clinical trials failed to go beyond early phase 2 studies because of limited efficacy. Various methods have been assessed to increase the potency of MSCs. IL-10 is an anti-inflammatory cytokine that is known to modulate immune responses in GvHD. In this study, we evaluated the feasibility of transfecting IL-10 mRNA to enhance MSC therapeutic potential. IL-10 mRNA engineered MSCs (eMSCs-IL10) maintained high levels of IL-10 expression even after freezing and thawing. IL-10 mRNA transfection did not appear to alter MSC intrinsic characteristics. eMSCs-IL10 significantly suppressed T cell proliferation relative to naïve MSCs in vitro. In a mouse model for GvHD, eMSCs-IL10 induced a decrease in plasma level of potent pro-inflammatory cytokines and inhibited CD4+ and CD8+ T cell proliferation in the spleen. In summary, our studies demonstrate the feasibility of potentiating MSCs to enhance their immunomodulatory effects by IL-10 mRNA transfection. The use of non-viral transfection may generate a safe and potent MSC product for treatment of clinical conditions associated with immune dysregulation such as GvHD.

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“…Current research shows that donor CD8 T cells are mainly activated by the recipient's hematopoietic APC, while donor CD4 T cells are activated by the recipient's gastrointestinal nonhematopoietic APC [ 73 , 74 ]. After that, the activated donor T cells are expanded into the Th1, Th2, and Th17/Tc17 subtypes [ 75 ].…”

Section: The Interaction Of Gut Microbiota and Gi Gvhdmentioning

confidence: 99%

A Promising Insight: The Potential Influence and Therapeutic Value of the Gut Microbiota in GI GVHD

Zhang

Chen

et al. 2022

Oxidative Medicine and Cellular Longevity

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Allogeneic hematopoietic cell transplantation (allo-HSCT) is a reconstruction process of hematopoietic and immune functions that can be curative in patients with hematologic malignancies, but it carries risks of graft-versus-host disease (GVHD), thrombotic microangiopathy (TMA), Epstein–Barr virus (EBV) infection, cytomegalovirus infection, secondary hemophagocytic lymphohistiocytosis (sHLH), macrophage activation syndrome (MAS), bronchiolitis obliterans, and posterior reversible encephalopathy syndrome (PRES). Gastrointestinal graft-versus-host disease (GI GVHD), a common complication of allo-HSCT, is one of the leading causes of transplant-related death because of its high treatment difficulty, which is affected by preimplantation, antibiotic use, dietary changes, and intestinal inflammation. At present, human trials and animal studies have proven that a decrease in intestinal bacterial diversity is associated with the occurrence of GI GVHD. Metabolites produced by intestinal bacteria, such as lipopolysaccharides, short-chain fatty acids, and secondary bile acids, can affect the development of GVHD through direct or indirect interactions with immune cells. The targeted damage of GVHD on intestinal stem cells (ISCs) and Paneth cells results in intestinal dysbiosis or dysbacteriosis. Based on the effect of microbiota metabolites on the gastrointestinal tract, the clinical treatment of GI GVHD can be further optimized. In this review, we describe the mechanisms of GI GVHD and the damage it causes to intestinal cells and we summarize recent studies on the relationship between intestinal microbiota and GVHD in the gastrointestinal tract, highlighting the role of intestinal microbiota metabolites in GI GVHD. We hope to elucidate strategies for immunomodulatory combined microbiota targeting in the clinical treatment of GI GVHD.

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GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

Cited by 32 publications

References 138 publications

Two Doses of BNT162b2 mRNA Vaccine in Patients after Hematopoietic Stem Cell Transplantation: Humoral Response and Serological Conversion Predictors

Two Doses of BNT162b2 mRNA Vaccine in Patients after Hematopoietic Stem Cell Transplantation: Humoral Response and Serological Conversion Predictors

IL-10 mRNA Engineered MSCs Demonstrate Enhanced Anti-Inflammation in an Acute GvHD Model

A Promising Insight: The Potential Influence and Therapeutic Value of the Gut Microbiota in GI GVHD

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