Acute Cryptococcal Immune Reconstitution Inflammatory Syndrome in a Patient on Natalizumab

Gundacker, Nathan; Jordan, Stephen J.; Jones, Benjamin A.; Drwiega, Joseph C.; Pappas, Peter G.

doi:10.1093/ofid/ofw038

Cited by 22 publications

(13 citation statements)

References 12 publications

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“…Not only in AIDS patients, C-IRIS is also reported in some multiple sclerosis (MS) patients. These MS patients had Cryptococcus infection prior to discontinuing Natalizumab treatment ( 12 ). Natalizumab is an integrin α4 antibody, which prevents T cell migration into the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

Th1-Dependent Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome Model With Brain Damage

et al. 2020

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Cryptococcus -associated immune reconstitution inflammatory syndrome (C-IRIS) is identified upon immune reconstitution in immunocompromised patients, who have previously contracted an infection of Cryptococcus neoformans ( Cn ). C-IRIS can be lethal but how the immune system triggers life-threatening outcomes in patients is still poorly understood. Here, we establish a mouse model for C-IRIS with Cn serotype A strain H99, which is highly virulent and the most intensively studied. C-IRIS in mice is induced by the adoptive transfer of CD4 + T cells in immunocompromised Rag1 -deficient mice infected with a low inoculum of Cn. The mice with C-IRIS exhibit symptoms which mimic clinical presentations of C-IRIS. This C-IRIS model is Th1-dependent and shows host mortality. This model is characterized with minimal lung injury, but infiltration of Th1 cells in the brain. C-IRIS mice also exhibited brain swelling with resemblance to edema and upregulation of aquaporin-4, a critical protein that regulates water flux in the brain in a Th1-dependent fashion. Our C-IRIS model may be used to advance our understanding of the paradoxical inflammatory phenomenon of C-IRIS in the context of neuroinflammation.

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Section: Introductionmentioning

confidence: 99%

Th1-Dependent Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome Model With Brain Damage

et al. 2020

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“…Thus, there was no evidence that PD-1 blockade in mice with fungal infection caused pneumonitis or any other form of immune reconstitution syndrome (48, 49) in a manner detrimental to the mice. Although we had correctly hypothesized that treatment would improve fungal clearance, it was possible that treatment might have enhanced susceptibility to infection; yet this did not occur.…”

Section: Discussionmentioning

confidence: 99%

Anti–PD-1 Antibody Treatment Promotes Clearance of Persistent Cryptococcal Lung Infection in Mice

Roussey

Viglianti

Teitz-Tennenbaum

et al. 2017

The Journal of Immunology

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Activation of immunomodulatory pathways in response to invasive fungi can impair clearance and promote persistent infections. The Programmed Cell Death Protein-1 (PD-1) signaling pathway inhibits immune effector responses against tumors and immune checkpoint inhibitors that block this pathway are being increasingly used as cancer therapy. The objective of the current study was to investigate whether this pathway contributes to persistent fungal infection and to determine whether anti-PD-1 antibody treatment improves fungal clearance. Studies were performed using C57BL/6 mice infected with a moderately virulent strain of Cryptococcus neoformans (52D) which resulted in prolonged elevations in fungal burden and histopathologic evidence of chronic lung inflammation. Persistent infection was associated with increased and sustained expression of PD-1 on lung lymphocytes, including a mixed population of CD4+ T cells. In parallel, expression of the PD-1 ligands, PD-L1 and PD-L2, was similarly upregulated on specific subsets of resident and recruited lung dendritic cells and macrophages. Treatment of persistently-infected mice for four weeks by repetitive administration of neutralizing anti-PD-1 antibody significantly improved pulmonary fungal clearance. Treatment was well tolerated without evidence of morbidity. Immunophenotyping revealed that anti-PD-1 antibody treatment did not alter immune effector cell numbers or myeloid cell activation. Treatment did reduce gene expression of IL-5 and IL-10 by lung leukocytes and promoted sustained upregulation of OX40 by Th1 and Th17 cells. Collectively, this study demonstrates that PD-1 signaling promotes persistent cryptococcal lung infection and identifies this pathway as a potential target for novel immune-based treatments of chronic fungal disease.

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“…Therapeutic interventions against autoimmune diseases are also strongly associated with susceptibility to infection. This is exemplified in patients undergoing treatment for multiple sclerosis (MS) who are at an increased risk of life-threatening Histoplasma capsulatum infections with the use of TNFα inhibitors, such as infliximab and etanercept ( 24 ), or increased risk of CNS infections with the very late antigen 4 (VLA-4) inhibitor, natalizumab, used for minimized autoimmune inflammation ( 25 , 26 ). A number of “off-target” epigenetic side effects have also been described that associate autophagy and epigenetics.…”

Section: The Balance Of Autophagy During Infection and Autoimmunitymentioning

confidence: 99%

Epigenetic Regulation of Autophagy: A Path to the Control of Autoimmunity

Hargarten

Williamson

2018

Front. Immunol.

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Autoimmune diseases are a significant cause of debilitation and mortality globally and are in need of cost-effective therapeutics. Autophagy is a cellular pathway that facilitates immune modulation involved in both pathogen control and autoimmunity. Regulation is multifactorial and includes a number of epigenetic pathways which can involve modification of DNA-binding histones to induce autophagy-related mRNA synthesis or microRNA and decapping-associated mRNA degradation which results in autophagy suppression. Appreciation of epigenetic-based pathways involved in autophagy and autoimmunity may facilitate application of a burgeoning group of epigenetic pharmaceuticals to these important diseases.

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Acute Cryptococcal Immune Reconstitution Inflammatory Syndrome in a Patient on Natalizumab

Cited by 22 publications

References 12 publications

Th1-Dependent Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome Model With Brain Damage

Th1-Dependent Cryptococcus-Associated Immune Reconstitution Inflammatory Syndrome Model With Brain Damage

Anti–PD-1 Antibody Treatment Promotes Clearance of Persistent Cryptococcal Lung Infection in Mice

Epigenetic Regulation of Autophagy: A Path to the Control of Autoimmunity

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