Immune checkpoint–directed antibodies increase survival in cancers

From NEJM review:

Immune checkpoint blockade is an increasingly important cancer treatment. Several studies have shown that it has a better safety profile than chemotherapy.

Immune checkpoint blockade increases antitumor immunity by blocking intrinsic down-regulators of immunity, such as:

- cytotoxic T-lymphocyte antigen 4 (CTLA-4) (1 antibody approved by FDA)
- programmed cell death 1 (PD-1) (2 antibodies)
- programmed cell death ligand 1 (PD-L1) (3 antibodies)

CTLA-4 inhibits an immune response in several ways, including attenuating T-cell activation at a proximal step in the immune response. In contrast, PD-1 inhibits T cells at later stages of the immune response in peripheral tissues.

Most of the toxic effects are reversible, aside from effects on the endocrine system, which may be permanent.

The NEJM review discussed the adverse effects of these medications in detail (see the link below).

References:

Immune-Related Adverse Events Associated with Immune Checkpoint Blockade — NEJM http://bit.ly/2qX9Nhc

Mechanisms of allergen immunotherapy for inhaled allergens: how does it work?

Allergen immunotherapy is effective in patients with IgE-dependent allergic rhinitis and asthma. When immunotherapy is given continuously for 3 years, there is persistent clinical benefit for several years after its discontinuation.

Clinical improvement is accompanied by decreases in numbers of effector cells in target organs, including:

- mast cells
- basophils
- eosinophils
- type 2 innate lymphoid cells


Mechanisms of allergen-specific immunotherapy (click to enlarge the image). The diagram is based on: Mechanisms of allergen-specific immunotherapy. Akdis CA, Akdis M. J Allergy Clin Immunol. 2011 Jan;127(1):18-27.

Immunotherapy results in:

- production of blocking IgG/IgG4 antibodies that can inhibit IgE-dependent activation mediated through both high-affinity IgE receptors (FcεRI) on mast cells and basophils and low-affinity IgE receptors (FcεRII) on B cells
- suppression of TH2 immunity can occur as a consequence of either deletion or anergy of antigen-specific T cells
- induction of antigen-specific regulatory T cells
- immune deviation in favor of TH1 responses.

It is not clear whether the altered long-term memory resides within the T-cell or the B-cell compartment. Recent data highlight the role of IL-10-producing regulatory B cells and "protective" antibodies that likely contribute to long-term tolerance.



References:

Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. - JACI 2017 - PubMed - NCBI http://bit.ly/2m5VEII

Is it safe to do skin tests with neuromuscular blocking agents (paralyzing agents) in outpatient setting in allergy clinic?

Adverse drug reactions affect up to 10% of people. When drug reactions resembling allergy happen, they are called drug hypersensitivity reactions (DHRs). Drug hypersensitivity reactions may be allergic or nonallergic. Drug allergies are drug hypersensitivity reactions caused by the immune system.

Is it safe to do skin tests with neuromuscular blocking agents (paralyzing agents) in outpatient setting in allergy clinic?

The evidence from multiple studies appears to show that skin tests with neuromuscular blocking agents (NMBAs, paralyzing agents) can be done safely in outpatient setting in allergy clinics.

A randomized trial included 111 healthy volunteers, in two centers specializing in France. Exclusion criteria were general anesthesia in the past; atopic diseases such as hay fever, childhood asthma, and atopic dermatitis; a history of hypersensitivity reactions; and known or suspected recent use of steroids, antidepressants, neuroleptics, or antihistamines.

The participants were randomly assigned to receive two NMBAs each. Negative and positive controls and five intradermal injections in increasing concentrations were administered on the forearms and on the back. Each subject received 28 injections.

Safety

There were three cases of pruritus after injection of one of the control or test substances. In one subject, this occurred after injection of histamine on the back. Two subjects had pruritus after injection of the highest concentration of atracurium. In one subject, this occurred both on the forearm and on the back. All of these events were mild to moderate and were self-limiting.



Drug allergy management in 5 steps (click to enlarge the image).



Classification of adverse drug reactions (ADR) (click to enlarge the image).

References

https://www.ncbi.nlm.nih.gov/pubmed/15041585
https://www.ncbi.nlm.nih.gov/pubmed/21375539
http://anesthesiology.pubs.asahq.org/article.aspx?articleid=2043034
http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1930957
http://www.adr-ac.ch/_m/cms_page_media/66/spoerl_Rocuronium%20allergy-short.pdf
https://pdfs.semanticscholar.org/8bb4/70ed2ac867420f257e7c0123b035ad3628d8.pdf

How getting older affects the immune system: Immunosenescence and “Inflammaging”

What is imunosenescence?

Immunosenescence is defined as the changes in the immune system associated with age.

The most important features of immunosenescence are:

- accumulation in “immunological space” of memory and effector cells
- this is caused by stimulation by repeated infections and exposure to antigens (inhalant allergens, food, etc.)

The state of chronic inflammation that characterizes senescence has an impact on survival and fragility.



Autoimmune conditions vs Immunodeficiency (click to enlarge the image).

What causes immunosenescence?

Immunosenescence is characterized by “remodelling” of the immune system, induced by oxidative stress (apoptosis plays a role in this):

- remodelling of apoptosis
- inflammaging
- up-regulation of immune response, secretion of pro-inflammatory lymphokines

What is inflammaging?

Aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as “inflammaging.” Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis.

Inflammaging is macrophage centered, involves several tissues and organs, including the gut microbiota, and is characterized by a complex balance between pro- and anti-inflammatory responses.

What causes “inflammaging”?

A possible cause of inflammaging is the continuous stimulation of macrophages by molecular garbage whose generation–disposal balance becomes impaired with age (‘Garb-aging’).

“Inflammaging” is also characterized by a decrease in “naive” T cells:

- reduction of CD8 virgins, CD4+ T cells and CD19+ B cells
- exhaustion of T cell-virgin (CD95−), which are replaced with the clonal expansion of CD28-T cells

How does inflammaging kill?

Increase of pro-inflammatory cytokines is associated with dementia, Parkinson’s disease, atherosclerosis, diabetes type 2, sarcopenia and a higher risk of morbidity and mortality.

Can we fix it?

A modulation of immune responses and apoptotic phenomena could be useful to reduce age-related degenerative diseases, as well as inflammatory and neoplastic diseases.

References:

Immunosenescence in aging: between immune cells depletion and cytokines up-regulation http://bit.ly/2DwcVC6
Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases | The Journals of Gerontology: Series A | Oxford Academic http://bit.ly/2DxzypH
Inflammaging and ‘Garb-aging’ http://bit.ly/2Clpxwl

Diamine oxidase test for evaluation of allergic diseases - helpful or not?

Based on a 2015 AAAAI review, diamine oxidase test is not helpful in the laboratory evaluation of allergic conditions (the text was edited below):

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There is insufficient information to validate the concept of histamine intolerance. Tests that are suggested include histamine infusion, histamine oral ingestion, red wine provocation; plasma histamine quantification; and measurement of the enzymes involved in the degradation of histamine (including Diamine oxidase). None of these can be recommended due to lack of information proving the predictive value of the tests.

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Histamine structure. Image source: Wikipedia.

References:

http://www.aaaai.org/ask-the-expert/histamine-intolerance
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