A new subcutaneous immune globulin (HyQvia) for primary immunodeficiency.
Med Lett Drugs Ther. 2015 Aug 31;57(1476):121-122
Authors:
PMID: 26305523 [PubMed – as supplied by publisher]
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Stanford Alliance for Primary Immunodeficiency
Stanford University
By Manish Butte
A new subcutaneous immune globulin (HyQvia) for primary immunodeficiency.
Med Lett Drugs Ther. 2015 Aug 31;57(1476):121-122
Authors:
PMID: 26305523 [PubMed – as supplied by publisher]
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By Manish Butte
Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.
J Exp Med. 2015 Aug 24;
Authors: Kreins AY, Ciancanelli MJ, Okada S, Kong XF, Ramírez-Alejo N, Kilic SS, El Baghdadi J, Nonoyama S, Mahdaviani SA, Ailal F, Bousfiha A, Mansouri D, Nievas E, Ma CS, Rao G, Bernasconi A, Sun Kuehn H, Niemela J, Stoddard J, Deveau P, Cobat A, El Azbaoui S, Sabri A, Lim CK, Sundin M, Avery DT, Halwani R, Grant AV, Boisson B, Bogunovic D, Itan Y, Moncada-Velez M, Martinez-Barricarte R, Migaud M, Deswarte C, Alsina L, Kotlarz D, Klein C, Muller-Fleckenstein I, Fleckenstein B, Cormier-Daire V, Rose-John S, Picard C, Hammarstrom L, Puel A, Al-Muhsen S, Abel L, Chaussabel D, Rosenzweig SD, Minegishi Y, Tangye SG, Bustamante J, Casanova JL, Boisson-Dupuis S
Abstract
Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
PMID: 26304966 [PubMed – as supplied by publisher]
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By Manish Butte
Cordycepin induced MA-10 mouse Leydig tumor cell apoptosis by regulating p38 MAPKs and PI3K/AKT signaling pathways.
Sci Rep. 2015;5:13372
Authors: Pan BS, Wang YK, Lai MS, Mu YF, Huang BM
Abstract
The p38 MAPKs play important roles in the regulation of balance between cell survival and cell death on the development of various cancers. However, the roles of p38 MAPKs regulating apoptotic effects on Leydig tumor cells remain unclear. In the present study, we showed that cordycepin (3′-deoxyadenosine) selectively induced apoptosis in MA-10 mouse Leydig tumor cells through regulating the p38 MAPK and PI3K/AKT signaling pathways. Cordycepin reduced viability in MA-10, TM4, and NT2/D1 cells, but not cause cell death of primary mouse Leydig cells on moderate concentration. Cordycepin increased reactive oxygen species (ROS) levels, which is associated with the induction of apoptosis as characterized by positive Annexin V binding, activation of caspase-3, and cleavage of PARP. Inhibition of p38 MAPKs activity by SB203580 significantly prevented cordycepin-induced apoptosis in MA-10 cells. Co-treatment with wortmannin or the autophagy inhibitor 3-methyladenine (3-MA) elevated levels of apoptosis in cordycepin-treated MA-10 cells. Moreover, cordycepin activated p53, p21 and TGFß; and downregulated CDK2. The antitumour activity of cordycepin-treated MA-10 cells was significantly distinct in severe combined immunodeficiency (SCID) mice in vivo. These results suggested that cordycein is a highly selective treatment to induce MA-10 cells apoptosis via p38 MAPKs signaling.
PMID: 26303320 [PubMed – in process]
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By Manish Butte
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Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body weight in obese patients.
Clin Exp Immunol. 2015 Jul;181(1):179-87
Authors: Hodkinson JP, Lucas M, Lee M, Harrison M, Lunn MP, Chapel H
Abstract
There are currently no data to support the suggestion that the dose of therapeutic immunoglobulin (Ig) should be capped in obese patients for pharmacokinetic (PK), safety and economic reasons. We compared IgG trough levels, increment and efficiency in matched pairs of obese and lean patients receiving either replacement or immunomodulatory immunoglobulin therapy. Thirty-one obese patients were matched with a clinically equivalent lean patient across a range of indications, including primary antibody deficiency or autoimmune peripheral neuropathy. Comprehensive matching was carried out using ongoing research databases at two centres in which the dose of Ig was based on clinical outcome, whether infection prevention or documented clinical neurological stability. The IgG trough or steady state levels, IgG increments and Ig efficiencies at times of clinical stability were compared between the obese and lean cohorts and within the matched pairs. This study shows that, at a population level, obese patients achieved a higher trough and increment (but not efficiency) for a given weight-adjusted dose compared with the lean patients. However at an individual patient level there were significant exceptions to this correlation, and upon sub-group analysis no significant difference was found between obese and lean patients receiving replacement therapy. Across all dose regimens a high body mass index (BMI) cannot be used to predict reliably the patients in whom dose restriction is clinically appropriate.
PMID: 25731216 [PubMed – indexed for MEDLINE]
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By Manish Butte
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[Severe atopy and allergy–rare hyper-IgE syndrome caused by the DOCK8 mutation as underlying condition].
Duodecim. 2015;131(6):541-4
Authors: Koskenvuo M, Kainulainen L, Vanto T, Lukkarinen H, Lähteenmäki P, Ruuskanen O
Abstract
The DOCK8 hyperimmunoglobulin E syndrome is an autosomal recessive primary combined immunological deficiency. Severe atopic eczema having its onset in infancy, food allergies, chronic viral infections of the skin, and recurrent pneumonias are central symptoms. Serum IgE level is high and eosinophilia is found in the blood. In addition, abnormalities in the number and function of lymphocytes can be detected. The disease may be difficult to distinguish from severe allergic eczema and asthma. The diagnosis is made through a gene test. We describe a 13-year-old boy, whose disease was cured with allogenic stem cell transplantation.
PMID: 26237897 [PubMed – indexed for MEDLINE]
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By Manish Butte
Successful Treatment of ANCA-Associated Vasculitis in the Setting of Common Variable Immunodeficiency Using Rituximab.
Am J Ther. 2015 Aug 18;
Authors: Hill F, Yonkof J, Chaitanya Arudra SK, Thomas J, Altorok N
Abstract
Autoimmune diseases such as idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia have a high reported prevalence in patients with common variable immunodeficiency (CVID). We describe the case of a 36-year-old Hispanic man with CVID treated with intravenous immunoglobulin, who developed antineutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis 15 years after immunodeficiency diagnosis. After failing first-line immunosuppressive therapy, the patient was successfully treated with rituximab. Although autoimmunity in the setting of CVID is well documented, this is the first report to describe a case of ANCA-associated vasculitis associated with CVID. Moreover, we report effective and safe use of rituximab in a patient with primary immunodeficiency.
PMID: 26291596 [PubMed – as supplied by publisher]
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By Manish Butte
A non-healing lesion in a 14-year old boy with primary immunodeficiency: a rare case of actinic keratosis affecting a child.
J Eur Acad Dermatol Venereol. 2015 Aug 20;
Authors: Balakirski G, Dueckers G, Niehues T, Megahed M
PMID: 26290047 [PubMed – as supplied by publisher]
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By Manish Butte
Facilitated Subcutaneous Immunoglobulin (fSCIg) Therapy – Practical Considerations.
Clin Exp Immunol. 2015 Aug 19;
Authors: Ponsford M, Carne E, Kingdon C, Joyce C, Price C, Williams C, El-Shanawany T, Williams P, Jolles S
Abstract
There is an increasing range of therapeutic options for primary antibody deficient patients who require replacement immunoglobulin. These include intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), rapid push SCIg and most recently recombinant human hyaluronidase facilitated SCIg (fSCIg). Advantages of fSCIg include fewer needle punctures, longer infusion intervals, and an improved adverse effect profile relative to IVIg. Limited real life experience exists concerning the practical aspects of switching or starting patients on fSCIg. We describe the first 14 patients who have been treated with fSCIg at the Immunodeficiency Centre for Wales (ICW), representing over 6 patient-years of experience. The regime was well tolerated with high levels of satisfaction and no increase in training requirement – including for a treatment-naive patient. Two patients discontinued fSCIg due to pain and swelling at the infusion site, and one paused therapy following post-infusion migraines. Ultrasound imaging of paired conventional and facilitated SCIg demonstrated clear differences in subcutaneous space distribution associated with a ten-fold increase in rate and volume delivery with fSCIg. Patient profiles for those choosing fSCIg fell into two main categories: those experiencing clinical problems with their current treatment and those seeking greater convenience and flexibility. When introducing fSCIg, consideration of the type and programming of infusion pump, needle gauge and length, infusion site, up-dosing schedule, home training and patient information are important as these may differ from conventional SCIg. This paper provides guidance on practical aspects of the administration, training and outcomes to help inform decision making for this new treatment modality. This article is protected by copyright. All rights reserved.
PMID: 26288095 [PubMed – as supplied by publisher]
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By Manish Butte
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Targeted Disruption of the β2-Microglobulin Gene Minimizes the Immunogenicity of Human Embryonic Stem Cells.
Stem Cells Transl Med. 2015 Aug 18;
Authors: Wang D, Quan Y, Yan Q, Morales JE, Wetsel RA
Abstract
: Human embryonic stem cells (hESCs) are a promising source of cells for tissue regeneration, yet histoincompatibility remains a major challenge to their clinical application. Because the human leukocyte antigen class I (HLA-I) molecules are the primary mediators of immune rejection, we hypothesized that cells derived from a hESC line lacking HLA-I expression could be transplanted without evoking a robust immune response from allogeneic recipients. In the present study, we used the replacement targeting strategy to delete exons 2 and 3 of β2-microglobulin on both gene alleles in hESCs. Because β2-microglobulin serves as the HLA-I light chain, disruption of the β2-microglobulin gene led to complete HLA-I deficiency on the cell surface of hESCs and their derivatives. Therefore, these cells were resistant to CD8(+) T-cell-mediated destruction. Although interferon-γ (IFN-γ) treatment significantly induced β2-microglobulin expression, promoting CD8(+) T cell-mediated killing of control hESCs and their derivatives, CD8(+) T-cell-mediated cytotoxicity was barely observed with β2-microglobulin-null hESCs and their derivatives treated with IFN-γ. This genetic manipulation to disrupt HLA-I expression did not affect the self-renewal capacity, genomic stability, or pluripotency of hESCs. Despite being relatively sensitive to natural killer (NK) cell-mediated killing due to the lack of HLA-I expression, when transplanted into NK cell-depleted immunocompetent mice, β2-microglobulin-null hESCs developed into tumors resembling those derived from control hESCs in severe combined immunodeficiency mice. These results demonstrate that β2-microglobulin-null hESCs significantly reduce immunogenicity to CD8(+) T cells and might provide a renewable source of cells for tissue regeneration without the need for HLA matching in the future.
SIGNIFICANCE: This study reports the generation of a novel β2-microglobulin (B2M)(-/-) human embryonic stem cell (hESC) line. Differentiated mature cells from this line do not express cell surface human leukocyte antigen molecules even after interferon-γ stimulation and are resistant to alloreactive CD8(+) T cells. Moreover, this B2M(-/-) hESC line contains no off-target integration or cleavage events, is devoid of stable B2M mRNA, exhibits a normal karyotype, and retains its self-renewal capacity, genomic stability, and pluripotency. Although B2M(-/-) hESC-derived cells are more susceptible to natural killer (NK) cells, murine transplantation studies have indicated that they are, overall, much less immunogenic than normal hESCs. Thus, these data show for the first time that, in vivo, the advantages provided by B2M(-/-) hESC-derived cells in avoiding CD8(+) T-cell killing appear significantly greater than any disadvantage caused by increased susceptibility to NK cells.
PMID: 26285657 [PubMed – as supplied by publisher]
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By Manish Butte
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Primary central nervous system lymphoma in Miyazaki, southwestern Japan, a human T-lymphotropic virus Type-1 (HTLV-1)-endemic area: clinicopathological review of 31 cases.
J Clin Exp Hematop. 2014;54(3):179-85
Authors: Maekawa K, Moriguchi-Goto S, Kamiunten A, Kubuki Y, Shimoda K, Takeshima H, Asada Y, Marutsuka K
Abstract
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive brain tumor. The aim of this study was to clarify the prevalence of T-cell-type PCNSL (T-PCNSL) in a human T-lymphotropic virus type-1 (HTLV-1)-endemic area of Southwestern Japan. We retrospectively investigated 31 PCNSL cases diagnosed between 1996 and 2013 at the University of Miyazaki Hospital. These cases accounted for 4.4% of all nodal or extranodal malignant lymphomas. Histologically, most of these cases were diagnosed as diffuse large B-cell lymphoma, while only two cases were considered to be low-grade and high-grade B-cell lymphoma (not otherwise specified). No T-PCNSL was found in this series. In addition, Epstein-Barr virus-encoded RNAs were not detected by in situ hybridization in any of the cases. Overall, no T-PCNSL cases were found in 18 years in a region with a high frequency of HTLV-1 seropositivity, namely, Southwestern Japan. This suggests that PCNSL and lymphomas of other anatomical sites are biologically distinct.
PMID: 25501108 [PubMed – indexed for MEDLINE]
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