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Posts Tagged ‘Allergy’


Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The importance of B cells to human health is more than what is already known. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts. B cells have been a subject of fascination since at least the 1800s. The notion of a humoral branch to immunity emerged from the work of and contemporaries studying B cells in the early 1900s.

 

Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory. This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells. Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants).

 

With so much already known, B cell biology might be considered ‘‘done’’ with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done.

 

Multiple self-tolerance checkpoints exist to remove autoreactive specificities from the B cell repertoire or to limit the ability of such cells to secrete autoantigen-binding antibody. These include receptor editing and deletion in immature B cells, competitive elimination of chronically autoantigen binding B cells in the periphery, and a state of anergy that disfavors PC (plasma cell) differentiation. Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring.

 

Autoantibodies are pathogenic in a number of human diseases including SLE (Systemic lupus erythematosus), pemphigus vulgaris, Grave’s disease, and myasthenia gravis. B cell depletion therapy using anti-CD20 antibody has been protective in some of these diseases such as pemphigus vulgaris, but not others such as SLE and this appears to reflect the contribution of SLPC (Short lived plasma cells) versus LLPC (Long lived plasma cells) to autoantibody production and the inability of even prolonged anti-CD20 treatment to eliminate the later. These clinical findings have added to the importance of understanding what factors drive SLPC versus LLPC development and what the requirements are to support LLPCs.

 

B cell depletion therapy has also been efficacious in several other autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis (RA). While the potential contributions of autoantibodies to the pathology of these diseases are still being explored, autoantigen presentation has been posited as another mechanism for B cell disease-promoting activity.

 

In addition to autoimmunity, B cells play an important role in allergic diseases. IgE antibodies specific for allergen components sensitize mast cells and basophils for rapid degranulation in response to allergen exposures at various sites, such as in the intestine (food allergy), nose (allergic rhinitis), and lung (allergic asthma). IgE production may thus be favored under conditions that induce weak B cell responses and minimal GC (Germinal center) activity, thereby enabling IgE+ B cells and/or PCs to avoid being outcompeted by IgG+ cells. Aside from IgE antibodies, B cells may also contribute to allergic inflammation through their interactions with T cells.

 

B cells have also emerged as an important source of the immunosuppressive cytokine IL-10. Mouse studies revealed that B cell-derived IL-10 can promote recovery from EAE (Experimental autoimmune encephalomyelitis) and can be protective in models of RA and type 1 diabetes. Moreover, IL-10 production from B cells restrains T cell responses during some viral and bacterial infections. These findings indicate that the influence of B cells on the cytokine milieu will be context dependent.

 

The presence of B cells in a variety of solid tumor types, including breast cancer, ovarian cancer, and melanoma, has been associated in some studies with a positive prognosis. The mechanism involved is unclear but could include antigen presentation to CD4 and CD8 T cells, antibody production and subsequent enhancement of presentation, or by promoting tertiary lymphoid tissue formation and local T cell accumulation. It is also noteworthy that B cells frequently make antibody responses to cancer antigens and this has led to efforts to use antibodies from cancer patients as biomarkers of disease and to identify immunotherapy targets.

 

Malignancies of B cells themselves are a common form of hematopoietic cancer. This predilection arises because the gene modifications that B cells undergo during development and in immune responses are not perfect in their fidelity, and antibody responses require extensive B cell proliferation. The study of B cell lymphomas and their associated genetic derangements continues to be illuminating about requirements for normal B cell differentiation and signaling while also leading to the development of targeted therapies.

 

Overall this study attempted to capture some of the advances in the understanding of B cell biology that have occurred since the turn of the century. These include important steps forward in understanding how B cells encounter antigens, the co-stimulatory and cytokine requirements for their proliferation and differentiation, and how properties of the B cell receptor, the antigen, and helper T cells influence B cell responses. Many advances continue to transform the field including the impact of deep sequencing technologies on understanding B cell repertoires, the IgA-inducing microbiome, and the genetic defects in humans that compromise or exaggerate B cell responses or give rise to B cell malignancies.

 

Other advances that are providing insight include:

  • single-cell approaches to define B cell heterogeneity,
  • glycomic approaches to study effector sugars on antibodies,
  • new methods to study human B cell responses including CRISPR-based manipulation, and
  • the use of systems biology to study changes at the whole organism level.

With the recognition that B cells and antibodies are involved in most types of immune response and the realization that inflammatory processes contribute to a wider range of diseases than previously believed, including, for example, metabolic syndrome and neurodegeneration, it is expected that further

  • basic research-driven discovery about B cell biology will lead to more and improved approaches to maintain health and fight disease in the future.

 

References:

 

https://www.cell.com/cell/fulltext/S0092-8674(19)30278-8

 

https://onlinelibrary.wiley.com/doi/full/10.1002/hon.2405

 

https://www.pnas.org/content/115/18/4743

 

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12911

 

https://cshperspectives.cshlp.org/content/10/5/a028795

 

https://www.sciencedirect.com/science/article/abs/pii/S0049017218304955

 

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Biological Therapeutics for Asthma

Curator: Larry H Bernstein, MD, FCAP

 

Update on Biological Therapeutics for Asthma

Marisha L. Cook, MD, and Bruce S. Bochner, MD
Department of Medicine, Division of Allergy and Clinical Immunology
Johns Hopkins University School of Medicine, Baltimore, MD

BASIC AND CLINICAL TRANSLATIONAL SCIENCE IN ALLERGY, ASTHMA AND IMMUNOLOGY
WAO Journal 2010; 3:188–194
Difficulty in managing severe asthma has encouraged research about its pathobiology and treatment options. Novel biologic therapeutics are being developed for the treatment of asthma and are of potential use for severe refractory asthma, especially where the increased cost of such agents is more likely justified. This review summarizes currently approved (omalizumab) and investigational biologic agents for asthma, such as

  • antibodies,
  • soluble receptors,
  •  other protein-based antagonists,

and highlight recent published data on efficacy and safety of these therapies in humans. As these newer agents with highly targeted pharmacology are tested in asthma,

  • we are also poised to learn more about the role of cytokines and other molecules in the pathophysiology of asthma.

Key Words: asthma, biologic therapies, cytokines, monoclonal antibodies

Despite the well-known and fairly consistent efficacy of
drugs such as inhaled corticosteroids, leukotriene modifiers
and 2 agonists for the majority of asthmatics, as many as
10% suffer from severe disease inadequately controlled by
conventional therapy. Severe and sustained symptoms lead to
poor quality of life, disproportionate use of health care

resources, and significant adverse effects. Novel biologic therapeutics are being developed for the treatment of asthma and are of potential use for severe refractory asthma, especially where the increased cost of such agents is more likely justified.
This review will briefly summarize what is meant by “biologic therapies” and then highlight recent published data on efficacy and safety of these therapies for asthma.

WHAT ARE BIOLOGIC THERAPIES?
Biologic therapies have revolutionized the treatment of many diseases including asthma. By definition, the term “biologics” or “biologicals” include a variety of protein based therapeutics, such as antibodies, soluble receptors (eg,etanercept), recombinant protein-based receptor antagonists (eg, pitrakinra) and other related structures. Their main advantages include the duration of action and highly specific and strong binding to the target of interest; their main disadvantages are the cost and need for parenteral administration. Most biologicals in clinical use are antibodies, and their generic names contain standard nomenclature as a suffix to
indicate their origins (Fig. 1). Initially, pure murine antibodies were created with hybridoma technology, generating therapies that were 100% mouse with generic names given the suffix “momab” (eg, ibritumomab); however, immunogenicity of mouse antibodies in human subjects caused reduced efficacy and increased risk of infusion reactions including anaphylaxis and death. To reduce immunogenicity, chimeric antibodies
(“ximabs” like rituximab) were engineered. These antibodies are a marriage of murine variable regions combined with human constant regions, creating antibodies that are 80% human. These were a step forward but still had the potential for being immunogenic. Humanized monoclonal antibodies (“zumabs” such as omalizumab) go one step further, where now only the hypervariable regions of the mouse antibody are retained,
while the remaining 95% of the antibody is molecularly replaced by human sequences.

In the latest approach, fully human antibodies (“umabs” such as adalimumab) can be created by using phage display technology and molecular biology or more directly by immunizing mice that have had their immunoglobulin genes replaced with human versions. Newer artificial antibody structures such as bispecific antibodies, mix 2 separate arms with 2 different binding specificities to target 2 different types of antigens [eg, a single antibody where one arm binds interleukin (IL)-4 and the other arm binds IL-13]. Standard nomenclature for mAbs identifies their source with the last 4 or 5 letters: -omab, murine: –ximab, chimeric: -zumab, humanized: and –umab, human. The middle part of the name reflects the disease indication for which the mAb was initially intended: -lim for immune and inflammatory diseases, -cir for cardiovascular disorders, and -tu for tumors or neoplastic conditions. The first 3 or 4 letters may be chosen by the sponsor. Modified (by adding the structure of a bispecific antibody) . In general, FDA-approved mAbs have emerged between 10 and 12 years after the date that the new technologies on which they were based were reported in the scientific literature. None of these newer antibody structures have been tried in asthma, so the remainder of this review will focus on available data with standard biologicals.
Here is a listing of the key focus on biomolecules for therapeutics:
IL-4    

It induces the IgE isotype switch and up-regulates expression of vascular cell adhesion molecule-1 on endothelium and a variety of TH2 chemokines, thus promoting recruitment of T lymphocytes, monocytes,                 basophils, and eosinophils to sites of allergic inflammation.  A clinical trial studied the soluble recombinant human IL-4 receptor (IL-4R), Nuvance in asthma. Nuvance inhibited a decline in FEV1 during inhaled corticosteroid withdrawal and was overall well tolerated.2,3 However, in subsequent clinical trials in patients taking only beta agonist, soluble IL-4R failed to demonstrate significant clinical efficacy. A phase I randomized double blind placebo controlled study evaluated the effects of pascolizumab, a humanized anti-IL-4 antibody, in 24 patients with mild to moderate asthma. Pascolizumab was well tolerated and no serious adverse events occurred.5 However, a phase IIa clinical trial in steroid-naive, mild to moderate asthmatics, did not demonstrate clinical efficacy. Because the IL-4 targeting studies have failed to demonstrate clinical efficacy, one can justify concluding that either IL-4R is not an effective therapeutic target in asthma.

TNFa

Tumor necrosis factor (TNF) is a multifunctional proinflammatory cytokine produced by inflammatory cells including monocytes, macrophages, mast cells, smooth muscle cells, and epithelial cells. TNF may initiate airway inflammation by up-regulating adhesion molecules, mucin hypersecretion, and airway remodeling, and by synergizing with TH2 cytokines. Berry et al demonstrated that severe refractory asthmatics have evidence of up-regulation of TNF as compared with healthy controls and mild asthmatics.  Entanercept was evaluated in a small, randomized, double-blind placebo-controlled crossover study in 10 patients with severe refractory asthma and elevated TNF levels, 10 patients with mild to moderate asthma, and 10 control patients. Entanercept treatment was associated with improved FEV1, asthma related quality of life, and the concentration of methacholine needed to provoke a 20% decrease in FEV1. No serious adverse reactions were noted. In another double-blind, placebo-controlled, parallel group study, 38 patients with moderate asthma on inhaled corticosteroids were treated with infliximab. Although infliximab treatment did not improve the primary end point of morning peak expiratory flow, it decreased diurnal variation of the peak expiratory flow rate and asthma exacerbations. No serious adverse events were noted. Golimumab was recently evaluated in the largest randomized, double-blind, placebo-controlled study in 309 patients with severe, uncontrolled asthma. No significant differences were observed for the change in FEV1 or exacerbations. However, several serious adverse events occurred. There is no clear role for TNF in perpetuating asthma or asthma exacerbations.

CD4

CD4 T cells are likely to be involved as a source of proinflammatory cytokines in asthma. Keliximab is a monoclonal antibody that causes a transient reduction in the number of CD4 T cells. A double blind, randomized, placebo controlled study with 22 severe oral corticosteroid dependent asthmatics patients was completed. A subset of patients received the highest dose of keliximab (3.0 mg/kg). There was significant improvement of peak expiratory flow rates in the high dose treatment arm. However, CD4 T cells remained transiently reduced 14 days postinfusion, raising safety concerns.

CD23  

CD23 is a low-affinity immunoglobulin E receptor (FcRII) and is important in regulating IgE production. IDEC-152 is a chimeric monoclonal antibody directed against CD23. CD23 is expressed on

  • T and B cells,
  • neutrophils,
  • monocytes, and
  • macrophages.

CD23 is overexpressed in allergic disease and may be involved in IgE overproduction,

    • which can lead to mast cell degranulation.

A phase I dose escalating placebo-controlled study in 30 asthmatics demonstrated that

  • IDEC-152 caused a dose-dependent reduction in serum IgE concentrations.
    • No significant adverse events were reported

CD25

Airway inflammation is associated with activated CD25 T cells, IL-2, and soluble IL-2 receptors. Daclizumab is a humanized monoclonal antibody directed against the alpha subunit of the high affinity IL-2 receptor (CD25). This inhibits IL-2 binding and release of inflammatory cytokines. A randomized, double-blind, placebo-controlled, parallel group study was performed (115 patients, 88 to the treatment arm, 27 to placebo)to evaluate the efficacy of daclizumab in patients with moderate to severe asthma poorly controlled on inhaled corticosteroids. Treatment with daclizumab led to improvements in FEV1, daytime asthma symptoms, and rescue 2 agonist use,but the effects were modest.

IgE

Omalizumab is a humanized monoclonal anti-IgE antibody that binds free circulating IgE and prevents the interaction between IgE and high affinity (FcRI) and low affinity (FcRII) IgE receptors on inflammatory cells. Omalizumab also down-regulates the surface expression of FcRI on basophils, mast cells, and dendritic cells.  Omalizumab decreases free IgE levels and reduces FcRI receptor expression on mast cells and basophils. This results in decreased mast cell activation and sensitivity, leading to a reduction in eosinophil influx and activation. Anti-IgE treatment with omalizumab might result in decreased mast cell survival. Omalizumab also reduces dendritic cell FcRI receptor expression.  The primary end point in a phase III randomized prospective trial was the number of exacerbation episodes during the steroid reduction period and the stable steroid period. During the stable steroid phase, fewer omalizumab subjects than placebo subjects experienced one or more exacerbations (14.6 vs. 23.3%; P  0.009). During the steroid reduction phase, the omalizumab group had fewer subjects with exacerbations (21.3 vs. 32.3%; P  0.04). The median reduction in inhaled corticosteroid dose was significantly greater in the omalizumab group than in the placebo group (75 vs. 50%; P  0.001).  The efficacy of omalizumab was demonstrated in other clinical trials including INNOVATE.  INNOVATE was a double-blind, parallel-group study in which 419 subjects were randomized to receive omalizumab or placebo for 28 weeks. The omalizumab group had a 26% reduction in the rate of clinically significant exacerbations compared with placebo (.68 vs. .91, P  0.042).  A recent omalizumab observational study of 280 subjects demonstrates similar findings. After 6 months, they found a reduction in daily symptoms by 80%, nocturnal symptoms by 86%, asthma exacerbations by 82%, hospitalizations by 76%, unscheduled health care visits by 81%, and improvement in quality of life (Mini Asthma Quality of Life Questionnaire increased from 2.9 to 4.5 after 6 months of treatment).

Examining the effects of biologic agents provides unique and valuable insight into the pathobiology of asthma. Furthermore, it is an ideal opportunity to identify mechanisms inherent to severe refractory asthma. The development of biologic agents has been a slow and arduous process; however, a substantial amount of progress has been achieved. Although omalizumab is an expensive medical treatment, therapy may be cost effective in patients with uncontrolled severe persistent allergic asthma because the majority of the economic burden is in this population. Hopefully ongoing efforts with biologicals will lead to improved management options for our most severe asthma patients.

More information is available from the article:    World Allergy Organ J. 2010;3(6):188–194.    http://dx.doi.org/10.1097/WOX.0b013e3181e5ec5a
PMCID: PMC2922052 NIHMSID: NIHMS221446
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922052/figure/F2/  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922052/bin/waoj-3-188-g002.gif  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922052/figure/F3/  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922052/bin/waoj-3-188-g003.gif
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922052/

English: Overview of hybridoma technology and ...

English: Overview of hybridoma technology and monoclonal antibody creation (Photo credit: Wikipedia)

Mast cells are involved in allergy. Allergies ...

Mast cells are involved in allergy. Allergies such as pollen allergy are related to the antibody known as IgE. Like other antibodies, each IgE antibody is specific; one acts against oak pollen, another against ragweed. (Photo credit: Wikipedia)

Emil von Behring

Emil von Behring (Photo credit: Wikipedia)

Diagram showing the production of monoclonal a...

Diagram showing the production of monoclonal antibodies via hybridoma technology (Photo credit: Wikipedia)

 

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