Questions and Answers in Allergy and Immunology

Editor: V. Dimov, M.D.

Most of the Questions and Answers have been selected from the Ask the Expert section of the AAAAI website.

Food Allergy

Anaphylaxis caused by inhalation of allergen. AAAAI, 05/2010.

Possible allergic reaction to rennet in cheese. AAAAI, 04/2010.

Avoidance of peanuts in a cashew-sensitive patient. AAAAI, 05/2010.
Educational posters for allergy to foods. AAAAI, 06/2010.

Urticaria

Treatment of difficult case of chronic idiopathic urticaria. AAAAI, 05/2010.

Treatment of chronic urticaria and abnormal thyroid function tests with levothyroxine. AAAAI, 06/2010.

Angioedema

Safety data on ecallantide, icatibant and C1 inhibitor use during pregnancy: category C. AAAAI, 07/2010.

Drug allergy

Sensitivity to Advil and perhaps other nonsteroidal antiinflammatory drugs in a patient with rheumatoid arthritis. AAAA, 04/2010.
Skin testing for penicillin and cephalosporin antibiotics. AAAAI, 04/2010.

Possible adverse reaction to HFA albuterol inhaler. AAAAI, 04/2010.

Desensitization to 5-aminosalicylic acid. AAAAI, 05/2010.

Possible anaphylaxis to oseltamivir (Tamiflu). AAAAI, 05/2010.

Possible allergy to trimethoprim. AAAAI, 05/2010.

Adverse reactions to HAART drugs used to treat HIV and AIDS. AAAAI, 05/2010.

Anaphylaxis to Cidex (ortho-phthalaldehyde) used to disinfect cystoscopy equipment. AAAAI, 06/2010.

History of allergic reaction to a sulfonamide antibiotic does not increase the specific risk of reacting to hydroxychloroquine (Plaquenil). AAAAI, 06/2010.

Possible reaction to ingestion of high dose ergocalciferol (vitamin D). AAAAI, 07/2010.

Allergic reactions to intravenous iron preparations. AAAAI, 08/2010.

Pregnant patient with a history of a local anesthetic reaction who must receive epidural. AAAAI, 08/2010.

Insect stings

Timing of skin testing after hymenoptera sting anaphylaxis. AAAAI, 05/2010.

Doses of venom utilized in venom immunotherapy. AAAAI, 05/2010.

Anaphylaxis to black ant, also called Chinese needle ant or giant needle ant. AAAAI, 07/2010.

Duration of venom immunotherapy to fire ant. AAAAI, 08/2010.

Skin prick test

Serotonin uptake inhibitors, for example, sertraline (Zoloft), do not affect the immediate hypersensitivity skin tests. AAAAI, 05/2010.

Omalizumab decreases skin test reactivity and specific IgEs. AAAAI, 06/2010.

Mucosal versus connective tissue mast cells. AAAAI, 06/2010.

What is the duration of effect of antihistamines on allergy skin tests? AAAAI, 07/2010.

Sensitivity of epicutaneous skin testing for foods. AAAAI, 08/2010.

Specific IgE or ImmunoCAP test

Omalizumab decreases skin test reactivity and specific IgEs. AAAAI, 06/2010.

Subcutaneous immunotherapy (SCIT)

Reactions to allergy injections. AAAAI, 04/2010.

Patients on ACE inhibitors receiving immunotherapy. AAAAI, 05/2010.

Increased incidence of immunotherapy reactions to aeroallergen immunotherapy administered by the rush technique. AAAAI, 05/2010.

Any side effects from inadvertent allergy injection containing an allergen to which the patient was not sensitive? AAAAI, 07/2010.

Contact dermatitis

Contact dermatitis to anti-aging moisturizer. AAAAI, 04/2010.

Contact dermatitis to tape adhesive. AAAAI, 05/2010.

Eosinophilic esophagitis

Eosinophilic esophagitis treatment with fluticasone - for how long?

Immunodeficiency

Antibody response (tieters) to pneumococcal vaccine. AAAAI, 05/2010.

What is an adequate response to pneumococcal immunization? AAAAI, 07/2010.

Is fever a contraindication to giving intravenous immunoglobulin (IVIG)? AAAAI, 06/2010.

Immunology

Workup of systemic mastocytosis. AAAAI, 06/2010.

Is Raynaud's Syndrome a Contraindication to Immunotherapy? AAAAI, 06/2010.

Vaccines and immunization

Antibody response (tieters) to pneumococcal vaccine. AAAAI, 05/2010.

What is an adequate response to pneumococcal immunization? AAAAI, 07/2010.

Anaphylaxis to human papillomavirus vaccine. AAAAI, 06/2010.

Urticaria angioedema after hapatitis B vaccination. AAAAI, 07/2010.

Medicolegal questions

Medical authorization consent forms for minors. AAAAI, 04/2010.

Ineffective or unapproved methods

Controversial techniques in allergy: the neutralization/provocation test. AAAAI, 04/2010.

Published: 04/22/2010
Updated: 08/10/2010

Interleukin-17 (IL-17)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

IL-17 is actually not one cytokine but a family of 6 related cytokines - promote tissue damage in autoimmune diseases and play a role in defense against bacterial infections.

Differentiation and maintenance of IL-17-producing T cell subset are dependent on TGF-β, IL-23, IL-6.

There was a theme issue of JACI on IL-17 and Th17 cells (PDF).

TH17 cells produce IL-17, IL-6, TNF, and IL-22. TH17 cells are important for neutrophil recruitment and they contribute to autoimmune disorders.

T(H)17 cells are the newest member of the T(H) cell family and are characterized by their ability to produce cytokines such as:

- IL-17
- IL-17F
- IL-22
- CCL20

T(H)17 cells are also associated with the development of:

- allergic contact dermatitis
- atopic dermatitis
- asthma


T helper cells (click to enlarge the image).

Autosomal dominant hyper-IgE syndrome, a rare primary immunodeficiency disorder, is caused by mutations of signal transducer and activator of transcription 3 (STAT3), preventing T(H)17 lineage differentiation and increasing susceptibility to Staphylococcus and Candida species infections.

Which cytokines promote neutrophil tissue inflammation?

(A) IL-2

(B) IL-5

(C) IL-8

(D) IL-10

(E) IL-17

Answers: IL-8 and IL-17.

References

Development and function of TH17 cells in health and disease. Louten J, Boniface K, de Waal Malefyt R. J Allergy Clin Immunol. 2009 May;123(5):1004-11.
Development and function of TH17 cells in health and disease. Louten J, Boniface K, de Waal Malefyt R. J Allergy Clin Immunol. 2009 May;123(5):1004-11.

Sarcoidosis is a Th1/Th17 multisystem disorder, Thorax 2011.

Published: 04/09/2010
Updated: 09/09/2011

Interleukin-13 (IL-13)

Author: V. Dimov, M.D., Allergist/Immunologist, Assistant Professor, University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist

Source: CD4+ T cells (TH2), NKT cells, mast cells

Receptors: Type I cytokine receptor family. Signal transduction involves Jak-STAT.

The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.

Erythropoietin (Epo) is produced in the kidney in response to low oxygen tension. Epo works through a type I cytokine receptor that signals through Jak2-STAT5.


(click to enlarge the image)

IL-13 is homologous to IL-4. Receptor distribution more limited: endothelial cells, B-cells, mononuclear phagocytes, and basophils - NOT mast cells or T-cells.

2 cognate receptors:

- IL-13Rα1 (low affinity by itself); paired with IL-4 receptor α (high affinity, signaling)
- IL-13Rα2 ( high affinity, decoy)

IL-13–induced TGF-β–mediated fibrosis is dependent on IL-13Rα2.

IL-13 binds to a low-affinity IL-13Ra2 subunit and a high-affinity complex comprised of IL-13Ra1 and IL-4Ra. Binding to this high-affinity complex leads to the phosphorylation-dependent activation of JAK1, JAK2 and STAT6.

IL-3 effects: IL-3 promotes the growth and development of mast cells from bone marrow.

IL-3 is a basophil differentiating cytokine vs. stem cell factor (c-Kit ligand) which is a mast cell growth factor.

IL-13 effects

- B cells: isotype switching to IgE
- Epithelial cells: increased mucus production
- Fibroblasts: increased collagen synthesis
- Macrophages: increased collagen synthesis

Medications

There are 3 humanized mAbs in phase I or phase II human clinical trials.

CAT-354 well tolerated in phase I trial, phase II trial is underway.

Genentech Pipeline: Lebrikizumab is a humanized monoclonal antibody that bind specifically to IL-13.

STAT6

STAT6 is the common transcription factor for both IL-4 and IL-13 signaling.

Therapeutic target via:

- a dominant-negative peptide
- anti-sense RNA-based approaches

References

Asthma Phenotypes and Interleukin-13 - Moving Closer to Personalized Medicine - NEJM, 2011.

Interleukin-13 Signaling and Its Role in Asthma, WAO Journal, 2011.

http://www.medimmune.com/pipeline/pipeline_phase2_detail.asp, Wynn, T. A. IL-13 effector functions. Annu. Rev. Immunol. 21, 425–456 (2003).

Andrews, A. L. et al. IL-13 receptor 2: a regulator of IL-13 and IL-4 signal transduction in primary human fibroblasts. J. Allergy Clin. Immunol. 118, 858–865 (2006).

Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

Bree, A. et al. IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys. J. Allergy Clin. Immunol. 119, 1251–1257 (2007).

McCusker, C. T. et al. Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT6 peptide. J. Immunol. 179, 2556–2564 (2007).

Popescu, F. D. Antisense- and RNA-interference-based therapeutic strategies in allergy. J. Cell Mol. Med. 9, 840–853 (2005).

Published: 04/09/2010
Updated: 09/09/2011

Interleukin-12 (IL-12)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: Macrophages, dendritic cells

Crystal structure of human IL-12, Wikipedia, public domain.

IL-12 effects

- T cells: TH1 differentiation
- NK cells and T cells: IFN-γ synthesis, increased cytotoxic activity

IL-12 is the main cytokine that activates STAT4.

IL-12 consists of two subunits - p35 and p40.

IL-12 binds to a type I receptor, composed of β1 and β2 subunits:

- p35 binds to β2 receptor, leading to Jak 2 activation and STAT4

- p40 binds to β1 receptor, leading toTyk 2 activation and STAT4

IL-12 sends a powerful signal to naive T cells, directing their differentiation to TH, shifting immune response towards cell-mediated immunity. In asthma, production of IL-12 by blood cells and expression in airway is impaired.

IL-18 is synergistic with IL-12.

Trials

Injection of rh IL-12 reduces circulating eosinophils in asthma. Treatment was not well tolerated: flu-like symptoms, abnormal LFTs and arrhythmias. Not actively developed as a therapy.

References

Bryan, SA, O'Connor, BJ, Matti, S, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356:2149.

Related reading

IL-12 in Wikipedia.

Ustekinumab is a Strong Option for Moderate to Severe Psoriasis - anti-IL12/23 monoclonal antibody with NNT of 2 http://goo.gl/gbXSJ

Published: 04/09/2010
Updated: 08/09/2011

Interleukin-10 (IL-10)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: Macrophages, T cells (mainly regulatory T cells)

IL-10 binds to a type II cytokine receptor, with Jak1 and Tyk2, Janus family kinases, which induce STAT3 signaling molecule.


(click to enlarge the image)

IL-10 effects

Macrophages, dendritic cells: inhibition of IL-12 production and expression of costimulators and class II MHC molecules

IL-10 has numerous functions:

- Inhibits eosinophil survival
- Inhibits IL-4 induced IgE synthesis
- Enhances IgG4 isotype switching
- Main inhibitory cytokine produced by T-reg cells in SCIT

Trials

In normal volunteers, IL-10 decreases CD4+ and CD8+ T cells, T-cell proliferation and endotoxin-driven TNF and IL-1beta production.

References

Recombinant human IL-10 currently being tested in RA, IBD, psoriasis, transplantation and hepatitis C. Chernoff, A. E. et al. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J. Immunol. 154, 5492–5499 (1995).

Cytokine Receptors

Neonatal BCG vaccination induces IL-10 production by CD4(+) CD25(+) T cells. http://goo.gl/grZJ

Published: 04/09/2010
Updated: 08/09/2010

Interleukin-9 (IL-9)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: Th2 cells.

Receptors: Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked SCID.


(click to enlarge the image)

IL-9 effects

Stimulates cell proliferation and prevents apoptosis.

Trials

Blocking IL-9 reduces airway hyperresponsiveness in mice. Phase I trials of IL-9 mAb (MEDI-528) completed. Phase II trials in progress for treating moderate to severe, persistent asthma.

References

http://www.medimmune.com/pipeline/pipeline_phase2_detail.asp. 'Byrne, P. et al. A single dose of MEDI-528, a monoclonal antibody against interleukin-19, is well tolerated in mild and moderate asthmatics in the phase II trial MI-CP-138. Chest 132, 478 (2007).

Published: 04/09/2010
Updated: 08/09/2010

Interleukin-7 (IL-7)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

IL-7 is a Type I family cytokine secreted by stromal cells in many tissues.

IL-7 stimulates survival and expansion of immature precursors committed to the B and T lymphocyte lineages.

IL-7 receptor consists of α chain associated with the γc chain (part of the receptors for IL-2, IL-4, and IL-15)

γc mutations lead to X-linked SCID. Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked

SCID.

Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).

Lack of a signal through which cytokine receptor accounts for the lack of T cell maturation in X-linked SCID?

A. IL-2

B. IL-7

C. IL-9

D. IL-15

E. IL-5

Answer: B.

References

Pending.

Published: 04/09/2010
Updated: 09/09/2010

Interleukin-5 (IL-5)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: CD4+ T cells (TH2).

Receptor: IL-5R heterodimer induces Jak2 and STAT 3 signaling pathway. The receptors for IL-3, IL-5, and GM-CSF share a common β chain. All 3 cytokines stimulate the development of eosinophils.

The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.


(click to enlarge the image)

IL-5 effects

- Eosinophils: activation, increased production
- B cells: proliferation, IgA production

IL-5 is the key regulator of eosinophil proliferation.

Mepolizumab (Bosatria)

Humanized mAb against IL-5. Promising results in hypereosinophilic syndrome and eosinophilic esophagitis. Larger trials ongoing. Disappointing early clinical trials in asthma. 2 asthma studies published in NEJM in March 2009.

Emerging appreciation of asthma heterogeneity. Identification of "eosinophilic asthma" with tissue eosinophils, greater airway remodeling, more exacerbations.

Three concepts in NEJM studies:

1. inhibition of IL-5 reduces eosinophilic inflammation

2. not all asthma is eosinophilic

3. reduction in eosinophils associated with a decreased rate of exacerbations

Unlike previous studies of anti-IL-5, the NEJM trials included patients highly eosinophilic asthma (sputum eosinophils gerater than 3%, 16% in one group).

Eosinophilic asthma occurs in less than 5% of adult-onset asthma.

Average age at asthma onset was the mid-to-late 20s. Screened hundreds to get 20 in one study. Reduction of eosinophils had no effect on FEV1, symptoms, and asthma control.

Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma, NEJM 2009

RCT, 61 subjects, sputum eosinophils greater than 3% despite high-dose ICS. Infusions of mepolizumab (29) or placebo (32) monthly for 1 year. Primary outcome: number of severe exacerbations. Secondary outcomes: symptoms, AQLQ (1-7), FEV1, airway hyperresponsiveness,eosinophils - blood and sputum.

Fewer severe exacerbations (2.0 vs. 3.4 per subject; relative risk, 0.57; P=0.02). Improvement in AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; P=0.02). Lower eosinophil counts in the blood (P lower than 0.001) and sputum (P=0.002). No significant differences: symptoms, FEV1, airway hyperresponsiveness.

Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984.

Mepolizumab for Prednisone-Dependent Asthma with Sputum Eosinophilia, NEJM 2009

RCT, persistent sputum eosinophilia (greater than 3%) and symptoms despite oral CS. Less than 3% of the 800 adult patients with severe asthma in the practice (McMaster University, Hamilton, ON, Canada). 9 patients received mepolizumab (5 monthly infusions), 11 placebo.

12 asthma exacerbations in 10 placebo patients. Only one mepolizumab patient had an exacerbation, not associated with sputum eosinophilia (P=0.002). Mepolizumab patients able to reduce prednisone dose by a mean of 84% of their maximum possible dose, as compared with 48±40.5% in placebo (P=0.04). Improvements in eosinophil numbers, asthma control, FEV1 for 8 weeks after last infusion.

Small pilot study.

Severe limitations:

- higher sputum eosinophil count at baseline in the mepolizumab group (16.6 vs 4)
- no significant difference in final prednisone doses in the two study groups
- most on LABAs: did not retest for albuterol reversibility or methacholine in all patients
- some investigators aware of study-group assignments - aware of sputum-cell counts

Nair P, Pizzichini MMM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;360:985-993

Receptors for each of the following cytokines share the common gamma chain except which one?

A. IL-2

B. IL-7

C. IL-9

D. IL-15

E. IL-5

Answer: E.

References

Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007;176:1062-1071.

Sally E. Wenzel, M.D. Eosinophils in Asthma — Closing the Loop or Opening the Door? NEJM, Volume 360:1026-1028, March 5, 2009, Number 10.

Monoclonal antibody reslizumab improves lung function in asthma subtype with eosinophilic airway inflammation - ACAAI, 2010. http://goo.gl/UJJHG

Anti-IL5 Antibody Reslizumb (mAb) Looks Promising for Severe Eosinophilic Asthma http://goo.gl/mlGkL

Azithromycin Inhibits IL-5 Production of T Helper Type 2 Cells from Asthmatic Children. http://1.usa.gov/171oIN

Published: 04/09/2010
Updated: 06/09/2011

Interleukin-4 (IL-4)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: CD4 T cells (TH2), mast cells.

The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.

Receptors: Type I cytokine receptor family which signals through the Jak-STAT pathway (STAT6). Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked SCID.


(click to enlarge the image)

IL-4 effects

- B cells: isotype switching to IgE
- T cells: TH2 differentiation, proliferation
- Macrophages: inhibition of IFN-gamma-mediated activation

- Mast cells: proliferation (in vitro)

IL-4 is the key cytokine for the IgE isotype switch.

Induction of VCAM -1, promotion of eosinophil migration, mucus production.

Th2 lymphocyte differentiation with subsequent release of additional IL-4, IL-5, and IL-13.

IL-4 and GATA3

IL-4 activates STAT6, which then engages the transcription factor GATA3, leading to secretion of IL-4. GATA3 is pivotal for Th2 maturation.

T-bet (also called TBX21 or T-box 21) is pivotal for Th1 maturation. T-bet inhibits IL-4, IL-5, and IL-17 secretion. T-bet may also inhibit Th2 differentiation by preventing GATA3 from interacting with its target DNA.

Oral synthesis inhibitors of IL-4

Suplatast tosilate inhibits the production of IL-4 and IL-5. In a study of asthmatic patients, there was an improvement in airway hyperresponsiveness, symptoms, and PEFR, and decreased IgE.

Soluble IL-4 receptor

Altrakincept is a recombinant, human IL-4 receptor - the extracellular portion. A small proof-of-concept trials of inhaled altrakincept in asthma showed promise but 2 larger trials failed to confirm efficacy - did not invalidate IL-4 as a target - there were concerns over the bioavailability of altrakincept in those trials.

IL-4Ra receptor antagonist (antibody)

AMG-317 is a fully human mAb antagonist to the IL-4Ra receptor - inhibits both IL-4 and IL-13 signaling). Developed by Amgen (hence the name "AMG") for treatment of allergic asthma.

AMG-317 (AAAAI abstract, March 09): 12-wk RCT, double-blind, 260 subjects with uncontrolled asthma, FEV1 50-80%. Randomized to 12 weekly injections of AMG 317 (75mg, 150mg, 300mg) or placebo. Primary endpoint was improvement in ACQ score.

At week 12, mean improvements in ACQ scores were: placebo (0.48), AMG 317 75mg (0.33), 150mg (0.56), and 300mg (0.65) (p=NS for all). Median improvement in total serum IgE was significantly greater in the 300mg AMG 317 group vs placebo. No AMG 317 treatment-related SAEs were reported.

Aerovant INH and Aeroderm IV

IL-4 mutein that inhibits the effects of both IL-4 and IL-13 through its ability to block IL-4Ra.

Aerovant (Pitrakinra) INH

Aerovant INH: Phase IIa, 30-patient study met its primary endpoint of reducing the severity of late asthmatic response by 72% percent (p lower than 0.001), BID for 27 days. Started in 2009: Phase IIb clinical trial of inhaled dry powder Aerovant in patients with uncontrolled asthma.

http://www.aerovance.com/press_132007.html
http://www.aerovance.com/press_030209.html

Aeroderm IV

PEGylated recombinant human IL-4 variant, block IL-4Ra.

Phase Iia in 24 patients with atopic dermatitis using a non-PEGylated form of the molecule (AER 001). Future studies will be in severe atopic eczema patients using the PEGylated form (AER 003).

http://www.aerovance.com/aeroderm.html

References

Hwang ES; Szabo SJ; Schwartzberg PL; Glimcher LH. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 2005 Jan 21;307(5708):430-3.

Tamaoki J, Kondo M, Sakai N, Aoshiba K, Tagaya E, Nakata J, et al. Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study. Lancet 2000;356:273-8.

Horiguchi T, Tachikawa S, Handa M, Hanazono K, Kondo R, Ishibashi A, et al.Effects of suplatast tosilate on airway inflammation and airway hyperresponsiveness. J Asthma 2001;38:331-6.

Yoshida M, Aizawa H, Inoue H, Matsumoto K, Koto H, Komori M, et al. Effect of suplatast tosilate on airway hyperresponsiveness and inflammation in asthma patients. J Asthma 2002;39:545-52.

Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 2001;107:963-70

Borish, LC, Nelson, HS, Lanz, MJ, et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 1999; 160:1816.

Wenzel, S, Wilbraham, D, Fuller, R, et al. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007; 370:1422.

J. Corren, W. Busse, E. Meltzer3, L. Mansfield4, G. Bensch5, Y. Chon6, M. Dunn6, H. Weng6, S. Lin. Efficacy and Safety of AMG 317, an IL-4Ra Antagonist, in Atopic Asthmatic Subjects: A Randomized, Double-blind, Placebo-controlled Study. JACI, Volume 123, Issue 3, Page 732 (March 2009).

Published: 04/09/2010
Updated: 08/09/2010

Interleukin-2 (IL-2)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: T cells, mostly CD4 T cells.

Receptor: IL-2 receptor is composed of 3 proteins: IL-2Rα, IL-2Rβ, γc. The receptor engages the Jak3-STAT5 signal transduction pathway. Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked

SCID.

Cytokine receptors (click to enlarge the image).

IL-2 effects

- T cells: proliferation, increased cytokine synthesis; potentiates Fas-mediated apoptosis; promotes regulatory T cell development, survival
- NK cells: proliferation, activation
- B cells: proliferation, antibody synthesis (in vitro)

Activation of Th2 cells by allergen leads to production of IL-2 and its receptor IL-2Ra.

Binding of IL-2 to Th2 cells expressing IL-2Ra leads to proliferation of that clone of specifically sensitized Th2 cells.

IL-2 promotes proliferation and survival of antigen specific T-cells, hence its old name “T-cell growth factor”.

Medications

Daclizumab (anti-CD25/IL-2Ra)

Humanized mAb approved for prevention of renal allograft rejection that binds to the alpha chain (CD25) of the IL-2 receptor on T cells. Inhibits IL-2–induced proliferation and reduces TH2 and TH1 cytokines from activated T cells. Humanized IL-2Ra or daclizumab (Zenapax) is used for prophylaxis of acute organ rejection in renal transplant patients.

Daclizumab was well tolerated in trials of asthma and was associated with clinical improvment. However, IL-2 has pleiotropic effects and caution is warranted in targeting this key cytokine.

Chimeric IL-2Ra or basiliximab

Chimeric IL-2Ra or basiliximab (Simulect) is used for prophylaxis of acute organ rejection in renal transplant patients.

Recombinant IL-2 (Proleukin)

Recombinant IL-2 (Proleukin) is used in the management of metastatic renal cell carcinoma and metastatic melanoma.

Suited to a T: Interleukin-2 as Therapy for Graft-versus-Host Disease - NEJM, 2011.

References

Busse, WW, Israel, E, Nelson, HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med 2008; 178:1002.

Desensitization protocols may overcome incompatibility barriers in renal transplantation, NEJM, 2011.

Published: 04/09/2010
Updated: 11/30/2011

Transforming Growth Factor-β (TFG-β)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

TGF-β was discovered as a tumor product that promoted the survival of cells.

Some regulatory T cells produce TGF-β, and the same cells may also produce IL-10, which also has immunosuppressive activities.

TGF-β inhibits the proliferation and effector functions of T cells and the activation of macrophages. Acts on neutrophils and endothelial cells to counteract the effects of pro-inflammatory cytokines.

TGF-β stimulates production of IgA by inducing B cells to switch to this isotype.

References

Cellular and Molecular Immunology, Abbas et al, 2009.

Published: 04/09/2010
Updated: 04/09/2010

Cytokine Receptors

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Cytokine Receptors include the following types:

- Type I (hematopoietin receptors - IL-3 and Epo)
- Type II
- IL-1 family receptors - they share Toll-like/IL-1 receptor (TIR) domain
- TNF receptors
- Seven-transmembrane α-helical receptors


(click to enlarge the image)

Type I Cytokine Receptors

Type I are hemopoietin receptors, contain a domain with two cysteine residues and a sequence of tryptophan-serine-X-tryptophan-serine (WSXWS), where X is any amino acid. Bind cytokines that fold into four α-helical strands - type I cytokines.

All type I and type II cytokine receptors engage Jak-STAT signaling pathways.

Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked SCID.

Type II Cytokine Receptors

Type II are similar to type I (two extracellular domains with conserved cysteines) but do not contain the WSXWS motif. These receptors consist of one ligand-binding polypeptide chain and one signal-transducing chain.

All type I and II cytokine receptors engage Jak-STAT signaling pathways.

IL-1 family receptors

IL-1 family receptors share a cytosolic sequence, called the Toll-like/IL-1 receptor (TIR) domain.

TNF receptors

TNF receptors are part of a large family of proteins (some of which are not cytokine receptors) with trimeric, cysteine-rich extracellular domains.

G protein-coupled receptors

Seven-transmembrane α-helical receptors are also called serpentine receptors, because their transmembrane domains "snake" back and forth through the membrane. Also called G protein-coupled receptors because their signaling pathways involve guanosine triphosphate (GTP)-binding proteins (G proteins). Involved in many types of cellular responses and typically produce a rapid and transient response.

References

Cellular and Molecular Immunology, Abbas et al., 2009.

Published: 04/09/2010
Updated: 08/14/2010

Interferon-gamma

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: T cells (TH1, CD8+ T cells), NK cells

Interferon-gamma effects

- Macrophages: activation (increased microbicidal functions)
- B cells: isotype switching to opsonizing and complement-fixing IgG subclasses
- T cells: TH1 differentiation
- Various cells: increased expression of class I and class II MHC molecules, increased antigen processing and presentation to T cells

Interferon-gamma suppresses TH2-cell-mediated allergic inflammation and suppresses allergic airway inflammation in animal models. It is induced during SCIT.

What is T-bet?

T-bet (also called TBX21 or T-box 21) is pivotal for Th1 maturation. STAT4 activates the transcription factor T-bet, which induces the secretion of IFN-gamma. T-bet promotes Th1 development by direct induction of IFN-gamma and IL-12Rbeta2 chain gene transcription. IFN-gamma acts an amplifier by binding to its receptor on Th1 cells and activating STAT1, which then engages T-bet.

T-bet inhibits IL-4, IL-5, and IL-17 secretion. T-bet may also inhibit Th2 differentiation by preventing GATA3 from interacting with its target DNA.

Potential treatment targets

T-bet: CpG antisense oligodeoxynucleotides

GATA3: GATA3-specific DNAzyme and CpG antisense oligodeoxynucleotides

Interferon-gamma therapy in asthma

Early studies of recombinant human IFN gamma gamma SQ in asthma were disappointing. One small study showed a reversal of the TH2-cell cytokine profile in severe asthma.

IFN beta therapy in asthma

Epithelial cells from asthmatics have an impaired protective IFNb response to infection with the common cold virus. Trials of recombinant human IFNb by inhalation to prevent severe virus-induced asthma exacerbations.

What is IGRA?

Interferon Gamma Release Assay (IGRA): used in any evaluation for TB infection (active or latent). It is more specific than TSTs (PPD), which may be positive with previous BCG or exposure to non-TB Mb. A positive test indicates TB infection. A negative test excludes TB in immunocompetent patients.

References

Hwang ES; Szabo SJ; Schwartzberg PL; Glimcher LH. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 2005 Jan 21;307(5708):430-3.

Boguniewicz, M. et al. The effects of nebulized recombinant interferon-γ in asthmatic airways. J. Allergy Clin. Immunol. 95, 133–135 (1995).

Simon, H. U., Seelbach, H., Ehmann, R. & Schmitz, M. Clinical and immunological effects of low-dose IFNα treatment in patients with corticosteroid-resistant asthma. Allergy 58, 1250–1255 (2003).

Wark, P. A. et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J. Exp. Med. 201, 937–947 (2005).

Contoli, M. et al. Role of deficient type III interferon-λ production in asthma exacerbations. Nature Med. 12, 1023–1026 (2006).

Holgate, S. T. Exacerbations: the asthma paradox. Am. J. Respir. Crit. Care Med. 172, 941–943 (2005).

Prognostic Value of a T-Cell–Based, Interferon- Biomarker in Children with Tuberculosis Contact Mustafa Bakir, MD; Kerry A. Millington, DPhil; Ahmet Soysal, MD; Jonathan J. Deeks, PhD; Serpil Efee; Yasemin Aslan, SRN; Davinder P.S. Dosanjh, DPhil; and Ajit Lalvani, DM. Annals of Int Med, 2 December 2008 | Volume 149 Issue 11 | Pages 777-786.

Neonatal BCG vaccination induces IL-10 production by CD4(+) CD25(+) T cells. http://goo.gl/grZJ

Related reading

Protective effect of BCG vaccination: time to reconsider the vaccination threshold? Thorax, 2010. http://goo.gl/nztVL

BCG vaccination: 90 years on and still so much to learn - Thorax http://goo.gl/2tyRj

Interferon regulatory factor 8 (IRF8) Mutations and Human Dendritic-Cell Immunodeficiency. NEJM, 2011.

Published: 04/09/2010
Updated: 04/09/2011

Tumor necrosis factor (TNF)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: Macrophages, T cells

TNF effects

- Endothelial cells: activation (inflammation, coagulation)
- Neutrophils: activation
- Hypothalamus: fever
- Liver: synthesis of acute phase proteins
- Muscle, fat: catabolism (cachexia)
- Many cell types: apoptosis

Proof of Concept

The success of TNF-α inhibitors in RA was "proof-of-concept" that inhibition of a single cytokine can be effective in treating a disease in which multiple cytokines are expressed, if that cytokine serves a central role. Inhibition of TNF in patients with asthma does not have the same effect seen in RA, has risks, and has taken a back seat in drug development.

Inhibitors of TNF-α

Most established clinical application of TNF inhibitors is in RA.

The anti-TNF-α strategies involve:

- anti-TNF-α antibody
- soluble TNF receptor

Five TNF inhibitors are used in clinical practice:

- Etanercept (Enbrel) - 2 TNF-alpha receptors coupled to the constant region of human IgG1 – a fusion protein.

- Infliximab (Remicade) - human constant region of IgG1 coupled to the variable regions of mouse anti-TNF-alpha – a chimeric (mouse/human) anti-TNF-alpha antibody (mAb).

- Adalimumab (Humira) - human mAb comprised of the human constant region of IgG1 attached to human variable regions - a fully human monoclonal anti-TNF-alpha antibody (mAb).

- Certolizumab (Cimzia) - antigen-binding fragement (Fab) of a humanized mAb coupled to polyethylene glycol.

- Golimumab (Simponi) -

Human IgG1κ

monoclonal

antibody specific

for human TNF-α.

Warnings

There is a risk of reactivation of TB or new infections with TNF inhibition. Tuberculin (TB) skin test with purified protein derivative (PPD) should be performed prior to initiation of therapy and annually.

Monitor for increase in liver function tests.

Vaccination with live vaccines is not recommended while patients are receiving TNF inhibitors.

Inhibitors of TNF-α for treatment of asthma

Inhibition of TNF in patients with asthma does not have the same dramatic effect seen in RA. Results of large-scale clinical trials with blockers of TNF-a have been disappointing. There was an increase in cancer risk.

It is possible that only a subset of severe asthmatics respond to anti-TNF therapy. Levels of expression of membrane-bound TNF-α by peripheral blood monocytes in such subjects with asthma may predict responses.

References

Berry M, Brightling C, Pavord I, Wardlaw AJ. TNF-alpha in asthma. Curr Opin Pharmacol 2007;7:279-82.

Brightling C, Berry M, Amrani Y. Targeting TNF-a a novel therapeutic approach for asthma. J Allergy Clin Immunol 2008;121:5-10.

Published: 04/09/2010
Updated: 09/09/2010

Cytokines

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

What is the difference between cytokine, interleukin and chemokine?

Cytokines (Greek cyto-, cell; and -kinos, movement) are substances secreted by cells of the immune system which carry signals locally between cells. They are proteins, peptides, or glycoproteins.

Interleukins are a group of cytokines first found to be expressed by white blood cells (leukocytes). The name is a misnomer since interleukins are produced by a wide variety of cells, not only leukocytes.

Chemokines (Greek -kinos, movement) are a family of small cytokines, or proteins secreted by cells. The name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines.

What is the number of FDA-approved immunomodulators for asthma as of April 2010?

One. Omalizumab (Xolair ®) (exclusing SCIT, of course).

What is a "classic" cytokine inhibitor that you use very often?

Glucocorticoids are potent transcriptional inhibitors and have been available for many years. Many effects of glucocorticoids: inhibition of NF-kB, adhesion molecule expression, arachidonic acid metabolism, metalloproteinase production, etc.

Related reading

Tumor necrosis factor (TNF)

Interferon-gamma

Transforming Growth Factor-β (TFG-β)

Interleukin-2 (IL-2)

Interleukin-4 (IL-4)

Interleukin-5 (IL-5)

Interleukin-7 (IL-7)

Interleukin-9 (IL-9)

Interleukin-10 (IL-10)

Interleukin-12 (IL-12)

Interleukin-13 (IL-13)

Interleukin-17 (IL-17)

Published: 04/09/2010
Updated: 04/22/2010

Treatment of Asthma

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children (JACI, 2011).

This is a very brief summary that will be updated.

Asthma classification and treatment for each stage.


Immunomodulators for allergic disorders, basic mind map.


Immunomodulators for allergic disorders, complete mind map.


Cytokine targets for immunomodulators for allergic disorders.

One of the changes between the asthma guidelines from 1997 (Second Expert Panel Report EPR2, 1997) and 2007 (Third Report, EPR3, 2007) is the concept of risk for future asthma.

Patients should continue their controller medications to reduce their future risk.

References

Immunomodulators for allergic respiratory disorders. Casale TB, Stokes JR. J Allergy Clin Immunol. 2008 Feb;121(2):288-96; quiz 297-8.


Asthma Inhalers - Factoring the Cost (click to enlarge the image).

Inhaled corticosteroid (ICS)

Relative binding affinity for glucocorticoid receptor (GR): mometasone > fluticasone > budesonide > triamcinolone.

Relative anti-inflammatory potency: mometasone = fluticasone > budesonide = beclomethasone > triamcinolone.

Related Reading

Pharmacotherapy of Mild Persistent Asthma - comprehensive review, 2011.

The Goals of Asthma Management. Dr. Neil Kao Allergy and Asthma Website, 2010.

Published: 04/04/2010
Updated: 07/04/2011