Manish Butte

Gene Therapy Approaches to Immunodeficiency.

September 13, 2017 By Manish Butte

Gene Therapy Approaches to Immunodeficiency.

Hematol Oncol Clin North Am. 2017 Oct;31(5):823-834

Authors: Ghosh S, Gaspar HB

Abstract
Transfer of gene-corrected autologous hematopoietic stem cells in patients with primary immunodeficiencies has emerged as a new therapeutic approach. Patients with various conditions lacking a suitable donor have been treated with retroviral vectors and a gene-addition strategy. Initial promising results were shadowed by the occurrence of malignancies in some of these patients. Current trials, developed in the last decade, use safer viral vectors to overcome the risk of genotoxicity and have led to improved clinical outcomes. This review reflects the progresses made in specific disorders, including adenosine deaminase deficiency, X-linked severe combined immunodeficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome.

PMID: 28895850 [PubMed – in process]

Opening Marrow Niches in Patients Undergoing Autologous Hematopoietic Stem Cell Gene Therapy.

September 13, 2017 By Manish Butte

Opening Marrow Niches in Patients Undergoing Autologous Hematopoietic Stem Cell Gene Therapy.

Hematol Oncol Clin North Am. 2017 Oct;31(5):809-822

Authors: Cowan MJ, Dvorak CC, Long-Boyle J

Abstract
Successful gene therapy for genetic disorders requires marrow niches to be opened to varying degrees to engraft gene-corrected hematopoietic stem cells (HSC). For example, in severe combined immunodeficiency, relatively limited chimerism is necessary for both T- and B-cell immune reconstitution, whereas for inborn errors of metabolism maximal donor chimerism is the goal. Currently, alkylating chemotherapy is used for this purpose. Significant pharmacokinetic variability exists in drug clearance in children less than 12 years old. Thus, pharmacokinetic monitoring is needed to achieve the targeted exposure goal for busulfan.

PMID: 28895849 [PubMed – in process]

Neutrophil Evolution and Their Diseases in Humans.

September 13, 2017 By Manish Butte

Neutrophil Evolution and Their Diseases in Humans.

Front Immunol. 2017;8:1009

Authors: Leiding JW

Abstract
Granulocytes have been preserved and have evolved across species, developing into cells that provide one of the first lines of host defense against pathogens. In humans, neutrophils are involved in early recognition and killing of infectious pathogens. Disruption in neutrophil production, emigration, chemotaxis, and function cause a spectrum of primary immune defects characterized by host susceptibility to invasive infections.

PMID: 28894446 [PubMed]

AQP8 transports NOX2-generated H2O2 across the plasma membrane to promote signaling in B cells.

September 13, 2017 By Manish Butte

AQP8 transports NOX2-generated H2O2 across the plasma membrane to promote signaling in B cells.

J Leukoc Biol. 2016 Nov;100(5):1071-1079

Authors: Bertolotti M, Farinelli G, Galli M, Aiuti A, Sitia R

Abstract
H2O2 acts as a second messenger in key signaling circuits, transiently modulating tyrosine phosphatases and kinases. We investigated its origin, membrane transport, and functional role during B cell activation and differentiation. Our data identified NADPH-oxidase 2 as the main source of H2O2 and aquaporin 8 as a transport facilitator across the plasma membrane. On aquaporin 8 silencing, inducible B lymphoma cells responded poorly to TLR and BCR stimulation. Their differentiation was severely impaired, as demonstrated by retarded onset of IgM polymerization, low amounts of IgM secretion, and prolonged BCR expression on the cell surface. A silencing-resistant aquaporin 8 rescued responsiveness, confirming that the import of H2O2 across the membrane is essential for B cell activation. The addition of exogenous catalase to primary B splenocytes severely impaired the tyrosine phosphorylation induced by BCR cross-linking, as did the absence of NOX2 in a murine model of chronic granulomatous disease. Importantly, re-expression of gp91(phox) through gene therapy restored the specific B cell signaling deficiency in NOX2(-/-) cells. Thus, efficient induction of B cell activation and differentiation requires intact H2O2 fluxes across the plasma membrane for signal amplification.

PMID: 27256569 [PubMed – indexed for MEDLINE]

Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency.

September 12, 2017 By Manish Butte

Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency.

J Clin Invest. 2017 May 01;127(5):1991-2006

Authors: Cottineau J, Kottemann MC, Lach FP, Kang YH, Vély F, Deenick EK, Lazarov T, Gineau L, Wang Y, Farina A, Chansel M, Lorenzo L, Piperoglou C, Ma CS, Nitschke P, Belkadi A, Itan Y, Boisson B, Jabot-Hanin F, Picard C, Bustamante J, Eidenschenk C, Boucherit S, Aladjidi N, Lacombe D, Barat P, Qasim W, Hurst JA, Pollard AJ, Uhlig HH, Fieschi C, Michon J, Bermudez VP, Abel L, de Villartay JP, Geissmann F, Tangye SG, Hurwitz J, Vivier E, Casanova JL, Smogorzewska A, Jouanguy E

Abstract
Inborn errors of DNA repair or replication underlie a variety of clinical phenotypes. We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation. The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic. We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients. The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice. The patients’ fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which was rescued by WT GINS1. The residual levels of GINS1 activity reached 3% to 16% in patients’ cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. The levels of GINS1 activity did not influence the immunological phenotype, which was uniform. Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency.

PMID: 28414293 [PubMed – indexed for MEDLINE]

Effect of reduced-intensity conditioning and the risk of late-onset non-infectious pulmonary complications in pediatric patients.

September 10, 2017 By Manish Butte

Effect of reduced-intensity conditioning and the risk of late-onset non-infectious pulmonary complications in pediatric patients.

Eur J Haematol. 2017 Sep 09;:

Authors: Nagasawa M, Mitsuiki N, Aoki Y, Ono T, Isoda T, Imai K, Takagi M, Kajiwara M, Kanegane H, Morio T

Abstract
OBJECTIVE: Late-onset non-infectious pulmonary complications (LONIPCs) contribute to higher morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we investigated the risk factors of LONIPCs in pediatric patients.
METHOD: Between 2001 and 2011, 74 pediatric patients (range, 7 months to 22.7 years old; median 6.5 years old), including 29 with a primary immunodeficiency underwent 80 allo-HSCTs at our institution. Sixty-seven patients who survived more than 3 months after allo-HSCT were analyzed retrospectively.The median follow-up period was 1 973 days (range, 126-5 145 days).
RESULTS: Nine patients (13.4%) developed LONIPCs between 90 and 3 578 days after allo-HSCT. A myeloablative conditioning (MAC) regimen and chronic GvHD were determined as significant risk factors of LONIPCs. None of 18 patients who received the reduced-intensity conditioning (RIC) regimen developed LONIPCs, although there was no difference in overall survival between the MAC and RIC regimen. Notably, two immunodeficient patients who received busulfan-based MAC regimen under two years old developed LONIPC with no history of chronic GvHD after 5 years and 10 years from SCT respectively, suggesting the direct toxicity of busulfan.
CONCLUSION: Our study’s findings indicate that the RIC regimen reduces the risk of LONIPCs in pediatric patients. This article is protected by copyright. All rights reserved.

PMID: 28888028 [PubMed – as supplied by publisher]

Advantages of Chinese medicine for patients with acquired immunodeficiency syndrome in rural central China.

September 10, 2017 By Manish Butte

Advantages of Chinese medicine for patients with acquired immunodeficiency syndrome in rural central China.

Chin J Integr Med. 2017 Sep 08;:

Authors: Xu QL, Guo HJ, Jin YT, Wang J, Jiang ZQ, Li ZW, Chen XM, Liu Y, Xu LR

Abstract
OBJECTIVE: To analyze the effect of Chinese medicine (CM) on mortality and quality of life (QOL) of acquired immunodeficiency syndrome (AIDS) patients treated with combined antiretroviral therapy (cART).
METHODS: A random sample of AIDS patients enrolled in the National Chinese Medicine Treatment Trial Program (NCMTP) that met the inclusion criteria was included in this study. NCMTP patients were included as the CM+cART group, and those not in the NCMTP were included as the cART group. Survival from September 2004 to September 2012 was analyzed by retrospective cohort study. QOL was analyzed by cross-sectional study.
RESULTS: The retrospective cohort study included 528 AIDS patients, 322 in the CM+cART group and 206 in the cART group. After 8 years, the mortality in the CM+cART group was 3.3/100 person-years, which was lower than the cART group of 5.3/100 person-years (P <0.05). The hazard ratio (HR) for mortality in the cART group was 1.6 times that of the CM+cART group by Cox proportional hazard model analysis. After controlling for gender, age, marital status, education, and CD4 T-cell count, the HR was 1.9 times higher in the cART group compared with the CM+cART group (P <0.05). The cross-sectional study investigated 275 AIDS patients. The mean scores of all QOL domains except spirituality/personal beliefs were higher in the CM+cART group than in the cART group (P <0.05).
CONCLUSIONS: For AIDS patients, CM could help to prolong life, decrease mortality, and improve QOL. However, there were limitations in the study, so prospective studies should be carried out to confirm our primary results.

PMID: 28887810 [PubMed – as supplied by publisher]

New therapeutic approach by sirolimus for enteropathy treatment in patients with LRBA deficiency.

September 9, 2017 By Manish Butte

New therapeutic approach by sirolimus for enteropathy treatment in patients with LRBA deficiency.

Eur Ann Allergy Clin Immunol. 2017 Sep;49(5):235-239

Authors: Azizi G, Abolhassani H, Yazdani R, Mohammadikhajehdehi S, Parvaneh N, Negahdari B, Mohammadi J, Aghamohammadi A

Abstract
Summary: Purpose. To report the successful use of sirolimus for management of enteropathy in four patients with LPS-responsive beige-like anchor protein (LRBA) deficiency. Methods. Case series. Results. sirolimus therapy led to a complete improvement of symptoms including decrease in frequency and severity of diarrhea, as well as patients’ weight gain. No signs of abdominal cramps and anorexia were also detected during the follow up period after treatment. Conclusions. sirolimus with its potential efficacy and immunomodulatory properties may be recommended for the treatment of severe enteropathy refractory to conventional therapy in patients with LRBA deficiency.

PMID: 28884992 [PubMed – in process]

Chronic Helicobacter cinaedi cellulitis diagnosed by microbial polymerase chain reaction.

September 9, 2017 By Manish Butte

Chronic Helicobacter cinaedi cellulitis diagnosed by microbial polymerase chain reaction.

JAAD Case Rep. 2017 Sep;3(5):398-400

Authors: Matsumoto A, Yeh I, Schwartz B, Rosenblum M, Schmidt TH

PMID: 28884138 [PubMed]

Deficiency in IRAK4 activity attenuates manifestations of murine Lupus.

September 9, 2017 By Manish Butte

Deficiency in IRAK4 activity attenuates manifestations of murine Lupus.

Eur J Immunol. 2017 May;47(5):880-891

Authors: Murphy M, Pattabiraman G, Manavalan TT, Medvedev AE

Abstract
Interleukin-1 receptor-associated kinase (IRAK) 4 mediates host defense against infections. As an active kinase, IRAK4 elicits full spectra of myeloid differentiation primary response protein (MyD) 88-dependent responses, while kinase-inactive IRAK4 induces a subset of cytokines and negative regulators whose expression is not regulated by mRNA stability. IRAK4 kinase activity is critical for resistance against Streptococcus pneumoniae, but its involvement in autoimmunity is incompletely understood. In this study, we determined the role of IRAK4 kinase activity in murine lupus. Lupus development in BXSB mice expressing the Y chromosome autoimmunity accelerator (Yaa) increased basal and Toll-like receptor (TLR) 4/7-induced phosphorylation of mitogen-activated protein kinases, p65 nuclear factor-κB (NF-κB), enhanced tumor necrosis factor (TNF)-α and C-C motif chemokine ligand (CCL) 5 gene expression in splenic macrophages, but decreased levels of Toll-interacting protein and IRAK-M, without affecting IRAK4 or IRAK1 expression. Mice harboring kinase-inactive IRAK4 on the lupus-prone Yaa background manifested blunted TLR signaling in macrophages and reduced glomerulonephritis, splenomegaly, serum anti-nuclear antibodies, numbers of splenic macrophages, total and TNF-α(+) dendritic cells, activated T- and B-lymphocytes, and lower TNF-α expression in macrophages compared with lupus-prone mice with functional IRAK4. Thus, IRAK4 kinase activity contributes to murine lupus and could represent a new therapeutic target.

PMID: 28295231 [PubMed – indexed for MEDLINE]