Efficacy, Safety and Tolerability of a New 10% Intravenous Immunoglobulin for the Treatment of Primary Immunodeficiencies.

We report here the results of a phase 3 study to assess the efficacy, safety, and tolerability of GC5107, a new 10% liquid intravenous immunoglobulin (IVIG) in preventing serious bacterial infections in patients with primary immunodeficiency (ClinicalTrials.gov: NCT02783482). Over a 12-month study period, 49 patients aged 3 to 70 years with a confirmed diagnosis of primary immunodeficiency received GC5107 at doses ranging from 319 to 881 mg/kg body weight every 21 or 28 days, according to their previous IVIG maintenance therapy.

Diagnosis and management of Specific Antibody Deficiency.

Specific antibody deficiency is a primary immunodeficiency disease recognized by the International Union of Immunology Societies and defined by recurrent respiratory infections with normal immunoglobulins, but diminished antibody responses to polysaccharide antigens after vaccination with the 23 valent pneumococcal polysaccharide vaccine. Clinical immunologists struggle with diagnosis and treatment, because the definition of an adequate response to immunization remains controversial. Specific antibody deficiency is managed clinically with close follow-up and prompt treatment of infections, antibiotic prophylaxis, or immune globulin therapy.

Immunoglobulin use in immune deficiency and autoimmune disease states.

Although immunoglobulin (Ig) has been available since the 1950s for replacement therapy in primary immune deficiency, many other effective uses of this class of biologics have been investigated and evolved over recent decades. Ig administration has become common practice in the treatment of the immunocompromised patient and has recently expanded into the treatment of those patients with an inflammatory disease and autoimmune neuropathies per established clinical guidelines. As research into the genetic basis of disease advances, clinicians should better assess complex data surrounding safe and effective uses of Ig to treat patients who present with B-cell and T-cell deficiencies, along with those harboring gene deletions or genetic anomalies who may potentially benefit from Ig therapy.

Update on the use of immunoglobulin in human disease: A review of evidence.

Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006.

Rare variants at 16p11.2 are associated with common variable immunodeficiency.

Background: Common variable immunodeficiency (CVID) is characterized clinically by inadequate quantity and quality of serum immunoglobulins with increased susceptibility to infections, resulting in significant morbidity and mortality. Only a few genes have been uncovered, and the genetic background of CVID remains elusive to date for the majority of patients.

Objective: We sought to seek novel associations of genes and genetic variants with CVID.

Fiscal implications of newborn screening in the diagnosis of severe combined immunodeficiency.

In the United States, newborn screening (NBS) is currently recommended for identification of 31 debilitating and potentially fatal conditions. However, individual states determine which of the recommended conditions are screened. The addition of severe combined immunodeficiency (SCID) screening to the recommended NBS panel has been fully instituted by 18 states, with another 11 states piloting programs or planning to begin screening in 2014.

Issues in solid-organ transplantation in children: translational research from bench to bedside.

In this review, we identify important challenges facing physicians responsible for renal and cardiac transplantation in children based on a review of the contemporary medical literature. Regarding pediatric renal transplantation, we discuss the challenge of antibody-mediated rejection, focusing on both acute and chronic antibody-mediated rejection. We review new diagnostic approaches to antibody-mediated rejection, such as panel-reactive antibodies, donor-specific cross-matching, antibody assays, risk assessment and diagnosis of antibody-mediated rejection, the pathology of antibody-mediated rejection, the issue of ABO incompatibility in renal transplantation, new therapies for antibody-mediated rejection, inhibiting of residual antibodies, the suppression or depletion of B-cells, genetic approaches to treating acute antibody-mediated rejection, and identifying future translational research directions in kidney transplantation in children.

Psychrobacter immobilis septicemia in a boy with X-linked chronic granulomatous disease and fulminant hepatic failure.

A 16-year old boy with chronic granulomatous disease (CGD) developed Psychrobacter immobilis septicemia during a course of fulminant hepatic failure. The patient died despite aggressive management with antimicrobials and corticosteroids. While Psychrobacter immobilis rarely affects humans, it should be considered an organism that can cause sepsis in patients with CGD.

Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5.

Since HIV requires CD4 and a co-receptor, most commonly C-C chemokine receptor 5 (CCR5), for cellular entry, targeting CCR5 expression is an attractive approach for therapy of HIV infection. Treatment of CD4(+) T cells with zinc-finger protein nucleases (ZFNs) specifically disrupting chemokine receptor CCR5 coding sequences induces resistance to HIV infection in vitro and in vivo. A chimeric Ad5/F35 adenoviral vector encoding CCR5-ZFNs permitted efficient delivery and transient expression following anti-CD3/anti-CD28 costimulation of T lymphocytes.

Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology.

A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications.

Local and national advocacy support.

Decisions by third-party payors that are restricting delivery of appropriate IgG treatment for primary immunodeficiency disease (PIDD) are summoning action from patients, physicians, and their organizations to ensure that high quality treatment remains accessible. Some of the strongest advocacy to date is from patient organizations, such as the Immune Deficiency Foundation (IDF), which strive to educate stakeholders on key issues that determine patient access to appropriate IgG treatment. These issues include the ability to choose the appropriate site of care based on a patient's experience and circumstance and greater awareness of product choice.

Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K.

Whole exome sequencing was used to determine the causative gene in patients with B cell defects of unknown etiology. A homozygous premature stop codon in exon 6 of PIK3R1 was identified in a young woman with colitis and absent B cells. The mutation results in the absence of p85α but normal expression of the p50α and p55α regulatory subunits of PI3K.

Genome-wide association identifies diverse causes of common variable immunodeficiency.

Background: Common variable immunodeficiency (CVID) is a heterogeneous immune defect characterized by hypogammaglobulinemia, failure of specific antibody production, susceptibility to infections, and an array of comorbidities.

Objective: To address the underlying immunopathogenesis of CVID and comorbidities, we conducted the first genome-wide association and gene copy number variation (CNV) study in patients with CVID.

Methods: Three hundred sixty-three patients with CVID from 4 study sites were genotyped with 610,000 single nucleotide polymorphisms (SNPs).

Genetic determinants in HIV-1 Gag and Env V3 are related to viral response to combination antiretroviral therapy with a protease inhibitor.

Objective: To identify novel viral determinants in HIV-1 protease, Gag, and envelope V3 that relate to outcomes to initial protease inhibitor-based antiretroviral therapy.

Design: A longitudinal cohort study of protease inhibitor-naive, HIV-infected individuals was designed to identify genetic variables in viral Gag and envelope sequences associated with response to antiretroviral therapy.

Methods: Genetic and statistical models, including amino acid profiles, phylogenetic analyses, receiver operating characteristic analyses, and covariation analyses, were used to evaluate viral sequences and clinical variables from individuals who developed immune reconstitution with or without suppression of viral replication.

Genetic engineering of T cells for adoptive immunotherapy.

To be effective for the treatment of cancer and infectious diseases, T cell adoptive immunotherapy requires large numbers of cells with abundant proliferative reserves and intact effector functions. We are achieving these goals using a gene therapy strategy wherein the desired characteristics are introduced into a starting cell population, primarily by high efficiency lentiviral vector-mediated transduction. Modified cells are then expanded using ex vivo expansion protocols designed to minimally alter the desired cellular phenotype.

Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases.

Homozygosity for the naturally occurring Delta32 deletion in the HIV co-receptor CCR5 confers resistance to HIV-1 infection. We generated an HIV-resistant genotype de novo using engineered zinc-finger nucleases (ZFNs) to disrupt endogenous CCR5. Transient expression of CCR5 ZFNs permanently and specifically disrupted approximately 50% of CCR5 alleles in a pool of primary human CD4(+) T cells.

Hypogammaglobulinemia in a pediatric tertiary care setting.

Hypogammaglobulinemia has been described as a secondary consequence of many disorders. It is also the seminal finding in many primary immune deficiencies. There are few studies examining the global etiologies of hypogammaglobulinemia.

Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).

The package inserts of live viral vaccines include immunodeficiency as a contraindication. Nevertheless, patients with mild forms of immunodeficiency may benefit from vaccination. No published guidelines exist for the administration of these vaccines specifically to patients with chromosome 22q11.

Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease.

Human immunodeficiency virus type 1 (HIV-1) protease activity is targeted at nine cleavage sites comprising different amino acid sequences in the viral Gag-Pol polyprotein. Amino acid polymorphisms in protease and in regions of Gag, particularly p7(NC) and the C-cleavage site between p2 and p7(NC), occur in natural variants of HIV-1 within infected patients. Studies were designed to examine the role of natural polymorphisms in protease and to identify determinants in Gag that modulate protease processing activity.