During the past two decades, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system. It is involved in the pathogenesis and control of infectious diseases, tumors, autoimmune processes and chronic degenerative diseases. Because of its variety of reaction partners (DNA, proteins, low–molecular weight thiols, prosthetic groups, reactive oxygen intermediates), its widespread production (by three different NO synthases (NOS) and the fact that its activity is strongly influenced by its concentration, NO continues to surprise and perplex immunologists. Today, there is no simple, uniform picture of the function of NO in the immune system. Protective and toxic effects of NO are frequently seen in parallel. Its striking inter- and intracellular signaling capacity makes it extremely difficult to predict the effect of NOS inhibitors and NO donors, which still hampers therapeutic applications.

Nitric oxide and the immune response

A clear picture of the dynamic relationship between the host immune system and cancer is emerging as the cells and molecules that participate in naturally occurring antitumour immune responses are being identified. The interferons (IFNs) - that is, the type I IFNs (IFNalpha and IFNbeta) and type II IFN (IFNgamma) - have emerged as central coordinators of tumour-immune-system interactions. Indeed, the decade-old finding that IFNgamma has a pivotal role in promoting antitumour responses became the focus for a renewed interest in the largely abandoned concept of cancer immunosurveillance. More recently, type I IFNs have been found to have distinct functions in this process. In this Review, we discuss the roles of the IFNs, not only in cancer immunosurveillance but also in the broader process of cancer immunoediting.

Interferons, immunity and cancer immunoediting.

Signaling through the JAK/STAT pathway, recent advances and future challenges.

https://www.cell.com/cell/pdf/S0092-8674(02)00701-8.pdf

Cytokine signaling in 2002: new surprises in the Jak/Stat pathway.

Universal and essential to cytokine receptor signaling, the JAK-STAT pathway is one of the best understood signal transduction cascades. Almost 40 cytokine receptors signal through combinations of four JAK and seven STAT family members, suggesting commonality across the JAK-STAT signaling system. Despite intense study, there remain substantial gaps in understanding how the cascades are activated and regulated. Using the examples of the IL-6 and IL-10 receptors, I will discuss how diverse outcomes in gene expression result from regulatory events that effect the JAK1-STAT3 pathway, common to both receptors. I also consider receptor preferences by different STATs and interpretive problems in the use of STAT-deficient cells and mice. Finally, I consider how the suppressor of cytokine signaling (SOCS) proteins regulate the quality and quantity of STAT signals from cytokine receptors. New data suggests that SOCS proteins introduce additional diversity into the JAK-STAT pathway by adjusting the output of activated STATs that alters downstream gene activation.

/pdf/the-jak-stat-signaling-pathway-input-and-output-integration-3rupzgudcd.pdf

The JAK-STAT Signaling Pathway: Input and Output Integration

Partial Impairment of Cytokine Responses in Tyk2-Deficient Mice

Background Subcutaneous immunoglobulin (IGSC) replacement therapy for primary immunodeficiency (PI) is equally efficacious to intravenous immunoglobulin (IGIV), induces fewer systemic reactions, and may be self-infused. Limited SC infusion volumes and reduced bioavailability, however, necessitate multiple infusion sites, more frequent treatment, and dose adjustment to achieve pharmacokinetic equivalence. Recombinant human hyaluronidase (rHuPH20) increases SC tissue permeability and facilitates dispersion and absorption, enabling administration of monthly doses in one site. Objective This study investigated the efficacy and tolerability of rHuPH20-facilitated IGSC (IGHy) in patients with PI. Methods In this open-label, multicenter phase III study, 87 patients with PI aged ≥2 years received 10% IGIV for 3 months, then IGHy (n = 83) for approximately 14 to 18 months at 108% of the IGIV dose. IGHy infusions began weekly, increasing to 3- or 4-week intervals. Results The majority (94.0%) of IGHy infusions were administered every 3 or 4 weeks, using one site (median, 1.09/month), with a mean volume of 292.2 mL. The bioavailability of IGHy measured by area under the concentration versus time curve was 93.3% of IGIV, which is pharmacokinetically equivalent. Systemic reactions were less frequent with IGHy than with IGIV (8.3% vs 25.0% of infusions). Local reactions to IGHy were generally mild to moderate, with a rate of 0.203 per infusion. The acute serious bacterial infection rate per subject-year for IGHy was low (0.025; upper 99% CI limit, 0.046). Overall infection rates per subject-year were 2.97 for IGHy and 4.51 for IGIV. Conclusion IGHy was effective, safe, and pharmacokinetically equivalent to IGIV at the same administration intervals, but it caused fewer systemic reactions. Tolerability was good despite high infusion volumes and rates.

https://www.jacionline.org/article/S0091-6749(12)01025-1/pdf

Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency.

Aim: To document the therapeutic efficacy and safety of Human Normal Immunoglobulin 10% Liquid (KIOVIG®/GAMMAGARD LIQUID® [IVIG 10%]) under clinical routine conditions. Patients & methods: Subjects received IVIG 10% according to the prescribing information and were followed for 6 ± 1 weeks to 12 ± 2 months depending on indication. Efficacy, adverse events, infusion rates and duration and dose were recorded. Results: Overall efficacy of IVIG 10% was rated as good or very good by the investigator in 81.8% of subjects; overall tolerability was good or very good in 87.5%. One serious adverse drug reaction (ADR) occurred (urticaria); no severe ADRs occurred. Conclusion: In this observational study, the efficacy and safety of IVIG 10% in routine clinical practice was similar to that previously reported in clinical studies.

Human immunoglobulin (KIOVIG®/GAMMAGARD LIQUID®) for immunodeficiency and autoimmune diseases: an observational cohort study.

Pharmacokinetics of Recombinant Human Hyaluronidase (rHuPH20)-Facilitated Subcutaneous Infusion of Immune Globulin (Human), 10% (IGHy) in Patients with Primary Immunodeficiency Disease (PI)

https://www.jacionline.org/article/S0091-6749(14)03028-0/pdf

Long-Term Efficacy and Safety of Recombinant Human Hyaluronidase (rHuPH20)- Facilitated Subcutaneous Infusion of Immunoglobulin G (IgG) (HyQvia; IGHy) in Patients with Primary Immunodeficiencies (PI)

Barbara McCoy

Papers

Partial Impairment of Cytokine Responses in Tyk2-Deficient Mice

Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency.

Human immunoglobulin (KIOVIG®/GAMMAGARD LIQUID®) for immunodeficiency and autoimmune diseases: an observational cohort study.

Pharmacokinetics of Recombinant Human Hyaluronidase (rHuPH20)-Facilitated Subcutaneous Infusion of Immune Globulin (Human), 10% (IGHy) in Patients with Primary Immunodeficiency Disease (PI)

Long-Term Efficacy and Safety of Recombinant Human Hyaluronidase (rHuPH20)- Facilitated Subcutaneous Infusion of Immunoglobulin G (IgG) (HyQvia; IGHy) in Patients with Primary Immunodeficiencies (PI)