SYK inhibitor entospletinib prevents ocular and skin GVHD in mice

Poe, Jonathan C.; Jia, Wei; Paolo, Julie A. Di; Reyes, Nancy; Kim, Ji Yun; Su, Hsuan; Sundy, John S.; Cardones, Adela R.; Pérez, Víctor L.; Chen, Benny J.; Chao, Nelson J.; Cardona, Diana M.; Saban, Daniel R.; Sarantopoulos, Stefanie

doi:10.1172/jci.insight.122430

Cited by 39 publications

(39 citation statements)

References 69 publications

(111 reference statements)

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“… 28 , 63 , 84 Entospletinib also reduces pulmonary inflammation by macrophages and increases Treg numbers, which might mitigate the lung damage seen in the later stages of severe COVID-19. 63 , 85 , 86 In a high-content screen for mucin-1–reducing compounds, a biochemical marker predicting ARDS, fostamatinib reduced mucin-1 in vitro and in vivo. 87 However, all SYK inhibitors reduce T- and B-cell frequency and activation, potentially impairing an adequate adaptive immune response.…”

Section: Immunomodulation In Relation To Sars-cov-2mentioning

confidence: 99%

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

Jacobs

Eldering²,

Kater

2021

Blood Advances

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Tyrosine kinase inhibitors (TKIs) are used to target dysregulated signaling pathways in virtually all hematologic malignancies. Many of the targeted signaling pathways are also essential in nonmalignant immune cells. The current coronavirus severe acute respiratory syndrome coronavirus 2 pandemic catalyzed clinical exploration of TKIs in the treatment of the various stages of COVID-19, which are characterized by distinct immune-related complications. Most of the reported effects of TKIs on immune regulation have been explored in vitro, with different class-specific drugs having nonoverlapping target affinities. Moreover, many of the reported in vivo effects are based on artificial animal models or on observations made in symptomatic patients with a hematologic malignancy who often already suffer from disturbed immune regulation. Based on in vitro and clinical observations, we attempt to decipher the impact of the main TKIs approved or in late-stage development for the treatment of hematological malignancies, including inhibitors of Bruton’s tyrosine kinase, spleen tyrosine kinase, BCR-Abl, phosphatidylinositol 3-kinase/ mammalian target of rapamycin, JAK/STAT, and FMS-like tyrosine kinase 3, to provide a rationale for how such inhibitors could modify clinical courses of diseases, such as COVID-19.

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Section: Immunomodulation In Relation To Sars-cov-2mentioning

confidence: 99%

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

Jacobs

Eldering²,

Kater

2021

Blood Advances

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“…A goal of vaccination is to generate long-lived memory B cells that can rapidly differentiate into ASCs upon re-exposure to antigens [18,19,23]. To determine influenza virus-specific antibody secreting cell responses, cells from the spleens and lungs were collected and incubated 5 days in 96 well plate coated with avian influenza A/Viet Nam/1203/2004(rgH5N1) inactivated virus.…”

Section: Resultsmentioning

confidence: 99%

Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs

et al. 2019

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Despite the ability to induce a broad range of cross protection, M2e5x virus-like particles (VLPs) alone provide limited vaccine efficacy and confer low efficacy of protection against highly pathogenic avian influenza virus (HPAIV) infection in chickens. Avian influenza hemagglutinin (HA) has been a major antigenic target that enhances humoral immunity, but the efficacy of avian HA-based vaccines against HPAIV needs to be further improved. In this study, we evaluated the vaccine efficacy induced by combination of conserved tandem repeat M2e5x VLPs and HA VLPs against an avian influenza virus. We found that combinatorial vaccine elicited higher levels of reassortant H5N1 (rgH5N1) virus-specific IgG, IgG1, IgG2a and IgA antibody responses compared to M2e5x VLPs in sera and lungs of mice. Combinatorial VLPs vaccination induced higher levels of CD8 + T cell and germinal center B cell responses in lung and spleen compared to M2e5x VLPs. Combinatorial VLPs vaccination showed significantly reduced inflammatory responses and lung viral loads upon rgH5N1 virus challenge infection, resulting in less body weight loss compared to M2e5x VLPs alone. These results indicate that immune responses to both M2e and HA might provide a strategy of vaccination inducing enhanced protection against avian influenza virus.

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“…Most importantly, we also aimed at revealing the gap in knowledge about the direct involvement of the meibomian gland and its dysfunction in oGvHD. From the papers reviewed [ 18 , 19 , 20 , 21 , 22 , 42 , 45 ], it is clear that much is known about the effects of aHSCT on the cornea, lacrimal gland, conjunctiva and its related goblet cells in terms of the development of oGvHD. Specifically, the immuno-inflammatory consequences associated of aHSCT on these ocular structures including the recruitment and infiltration of neutrophils, monocytes, macrophages, T-cells (CD3+, CD4+, CD8+) and upregulation of certain inflammatory cytokines including interleukin-6, interferon- γ and tumor necrosis factor-alpha which are known to modulate ocular surface disease.…”

Section: Discussionmentioning

confidence: 99%

“…There are few established pre-clinical animal models of oGvHD [ 18 , 19 , 20 , 21 , 22 , 42 , 45 ]. Reports on such models show considerable differences especially in donor-recipient matching and mode of induction of GvHD, therefore differences in oGvHD and outcomes of interest measured.…”

Section: Pre-clinical Models Of Ogvhd and The Meibomian Glandmentioning

confidence: 99%

“…Thus, necessitating future (suitable) models to consider direct investigations of the meibomian gland, its dysfunction and contribution to the development of oGvHD. A summary of relevant studies on pre-clinical models of oGvHD with their key findings is presented in Table 1 [ 18 , 19 , 20 , 21 , 22 , 42 , 45 ].…”

Section: Pre-clinical Models Of Ogvhd and The Meibomian Glandmentioning

confidence: 99%

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Meibomian Gland Dysfunction in Ocular Graft vs. Host Disease: A Need for Pre-Clinical Models and Deeper Insights

Osae

Steven

2021

IJMS

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Despite decades of experience with hematopoietic stem cell transplantation, we are still faced with the delicate equipoise of achieving stable ocular health post-transplantation. This is because ocular graft-versus-host disease (oGvHD) following hematopoietic stem cell transplantation frequently occurs (≥50%) among transplant patients. To date, our understanding of the pathophysiology of oGvHD especially the involvement of the meibomian gland is still limited as a result of a lack of suitable preclinical models among other. Herein, the current state of the etiology and, pathophysiology of oGvHD based on existing pre-clinical models are reviewed. The need for additional pre-clinical models and knowledge about the involvement of the meibomian glands in oGvHD are emphasized.

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SYK inhibitor entospletinib prevents ocular and skin GVHD in mice

Cited by 39 publications

References 69 publications

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

Influenza M2 virus-like particle vaccination enhances protection in combination with avian influenza HA VLPs

Meibomian Gland Dysfunction in Ocular Graft vs. Host Disease: A Need for Pre-Clinical Models and Deeper Insights

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