Medical Journal Review

Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief and Guest Reviewer Gary Hellermann, PhD

1. AUTOLOGOUS NONMYELOABLATIVE HEMATOPOIETIC STEM CELL TRANSPLANTATION (AHST) IN NEWLY DIAGNOSED TYPE 1 DIABETES MELLITUS
Guest Reviewer: Gary Hellermann, PhD
Type 1 diabetes mellitus (DM) is one of the most common autoimmune diseases and researchers have been attempting to circumvent the immune system’s destruction of pancreatic beta cells that characterizes the disease. One promising method is by AHST. This paper reports the results of a clinical trial in which 15 newly diagnosed DM patients, age 14-31 years, were given AHST and the progress of their disease followed for up to 36 months. All but one showed marked improvement as reflected by elevated C-peptide levels and freedom from insulin use. Side effects were neutropenia, alopecia, nausea and, in one case, pneumonia that resolved with treatment. Editor’s comment: Immunointervention in type 1 DM at a young age while there is still a substantial number of beta cells appears to provide significant advantages, but long term side-effects still need to be examined. Voltarelli, JC et al. JAMA 2007; 297:1568.

2. JACI AND ALLERGEN IMMUNOTHERAPY
The April 2007 JACI has multiple reviews and featured articles on allergen immunotherapy. The articles entitled are "Allergen Immunotherapy: Where Is It Now?," "Mechanisms of Allergen-Specific Immunotherapy," "Tradition and Innovation: Finding the Right Balance," and "Sublingual Immunotherapy: The Optimism and the Issues." In addition, there are articles entitled, "Recombinant Allergens For Immunotherapy," "Advances In Upper Airway Diseases and Allergen Immunotherapy," and "Allergic Rhinitis and Its Impact on Asthma Update: Allergen Immunotherapy." Likewise, there are three original articles on immunotherapy which include "Sublingual Immunotherapy With Grass Pollen Is Not Effective In Symptomatic Youngsters In Primary Care," "Update On the Current Status Of Peptide Immunotherapy," and "Successful Sublingual Immunotherapy With Birch Pollen Has Limited Effects On Concomitant Food Allergy To Apple and the Immune Response To the Bet v 1 homolog Mal d 1." Editor’s comment: This issue contains a multitude of articles on allergen immunotherapy and is must reading for the practicing allergist/immunologist. Nelson HS; Akdis M, et al; Durham SR; Pajno GB; Valenta R, et al; Nelson HS; Passalacqua G, et al; Röder E, et al; Larché M; Kinaciyan T, et al. JACI 2007; 119(4).

3. INDACATEROL (I), A NOVEL INHALED β2-AGONIST, PROVIDES SUSTAINED 24-H BRONCHODILATION IN ASTHMA
42 patients were randomized to receive single doses of I (50, 100, 200 and 400 μg) or placebo (P) via a hydrofluoroalkane pressurized metered-dose inhaler in a double-blind crossover study. Using primary efficacy comparisons, the mean percentage increases in FEV₁ from placebo (P) and I, 200 and 400 μg, were 7.6 and 14.9%, respectively, at 30 min and 7.5% and 10.4%, respectively, at 21 h post-dose. At these doses, changes in mean FEV₁ of I vs. P were significant from 5 min to 24 h, inclusive. I at 400 μg was statistically superior (P < 0.05) to other I doses at most time points. The highest mean differences in FEV₁ of I from P were reached at 2-3 h post-dose. Once daily I (200 and 400 μg) provides 24-h bronchodilation, rapid onset, and good tolerability and safety. Editor’s comment: 24-h long-acting bronchodilators are on their way. Beeh KM, et al. Eur Respir J 2007; 29:871.

4. EXHALED AIR TEMPERATURE IN ASTHMA: METHODS AND RELATIONSHIP WITH MARKERS OF DISEASE
57 children, 41 allergic mild asthmatics and 16 healthy controls, underwent exhaled air temperature and lung function measurements. The asthmatic children also underwent exhaled nitric oxide (NO) measurement and hypertonic saline sputum induction for eosinophils. Exhaled temperatures were significantly higher in asthmatics than controls (30.18 ± 0.14 ºC vs. 27.47 ± 0.24 ºC (P < 0.001). There was a positive relationship between exhaled air temperature and both NO (r = 0.39; P = 0.01) and % EOS (r = 0.53; P = 0.04). The authors conclude that exhaled breath temperature is related to airway inflammation in asthma. Editor’s comment: Another article indicating that there is correlation between exhaled breath temperature and inflammation in asthma. Piacentini GL, et al. Clin Exp Allergy 2007; 37: 415.

5. RESPIRATORY HEAT AND MOISTURE LOSS (RHML) IS ASSOCIATED WITH EOSINOPILIC INFLAMMATION IN ASTHMA
23 subjects with asthma and 18 controls had RHML measured in a cross-sectional study using a device that combines temperature and humidity measurements during inspiration and expiration and allows precise control over inspiratory conditions and ventilatory pattern. They also underwent parallel measurements of exhaled NO (eNO), % sputum eosinophilia and exhaled breath condensate pH. Mean ±SD RHML was elevated in asthma (98.1±7.3 J·L-¹) vs controls (91.9±4.5 J·L-¹). The results correlated with % sputum eosinophilia (r = 0.73, P<0.0001) but not with eNO, EBC pH, FEV₁ or FEV₁ % predicted. Editor’s comment: Respiratory heat and moisture loss are elevated in patients with asthma. Noble DD, et al. Eur Respir J 2007; 29:676.

6. TIOTROPIUM (T) IN COMBINATION WITH PLACEBO (P), SALMETEROL (S), OR FLUTICASONE – SALMETEROL (FS) FOR TREATMENT OF COPD
This is a randomized, double-blind, placebo-controlled trial of 449 patients with moderate to severe COPD. They were treated for 1 year with T plus placebo (P), T + S, or T + FS. The primary end point was the number who experienced COPD exacerbations that required treatment with systemic steroids or antibiotics. The proportion of patients who experienced exacerbations did not differ in the 3 groups. T + FS improved lung function (P = 0.049) and disease-specific QOL (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation and all-cause hospitalizations [incidence rate ratio, 0.67 (CI, 0.45 to 0.99)] compared with T + P. In contrast, T + S did not statistically improve lung function or hospitalization rates compared with T + P. The authors conclude that FS + T did not influence COPD exacerbation rates but did improve lung function, QOL, and hospitalization rates in patients with moderate to severe COPD. Editor’s comment: The jury is still out as to the best treatment for moderate to severe COPD. Physicians have to individualize treatment of COPD and what is appropriate and cost-effective for one patient may not be so for another. Aaron SD, et al. Ann Intern Med 2007; 146:545. Editorial, Criner GJ: 606.

7. NEWS FOCUS IMMUNOLOGY: THE EDUCATION OF T CELLS
Guest Reviewer: Gary Hellermann, PhD
When T lymphocytes are activated by antigen-presenting cells, they also receive instructions where to go. From the lymphoid tissue, they migrate to the exact area of the body under attack to play their part in the immune response. What are the signals that tell them this and where do they come from? Dendritic cells are the key because they identify the molecular address of the tissue in which the antigen was acquired and pass this information along to the T cell in the form of a pattern of chemokine receptors and cell-adhesion molecules. Editor’s comment: This clearly written review tells the story of how T cells are "educated" to home to a specific tissue address. Ferber, D. Science 2007; 316:191.

8. FOXP3 CONTROLS REGULATORY T-CELL FUNCTION BY INTERACTING WITH AML1/RUNX1
Guest Reviewer: Gary Hellermann, PhD
The key molecule that distinguishes a regulatory T cell is the transcription factor, Foxp3, which acts to maintain self-tolerance and suppress an overactive immune response. The molecular basis of Foxp3 function is a hot area of research, and the pieces of the puzzle are quickly falling into place. Suppression of IL-2 production by regulatory T cells is one aspect of Foxp3 control, and this article demonstrates by a masterful series of experiments that control is exerted directly through inhibition of the IL-2 transcription activator, AML1/Runx1 (acute myeloid leukaemia 1/Runt-related transcription factor. Editor’s comment: Foxp3 is the heavy hitter in regulatory T cells and this article adds one more to its list—suppression of IL-2 gene expression. Ono, M et al. Nature 2007; 446:685.

9. AIRWAY SMOOTH MUSCLE (ASM) DYNAMICS: A COMMON PATHWAY OF AIRWAY OBSTRUCTION IN ASTHMA
This multi-authored paper reviews airways smooth muscle (ASM) dysfunction and its contribution to the pathophysiology of asthma. It indicates that there is a central role for ASM in the pathogenesis of airway hyperresponsiveness. Editor’s comment: This American Thoracic Society Workshop Report is extremely interesting and an in-depth discussion of the complex issues surrounding ASM and asthma. An SS, et al. Eur Respir J 2007; 29:834.

10. OSTEOIMMUNOLOGY
Osteoimmunology is an interdisciplinary research involving osteology (the branch of anatomy that deals with the structure and function of bones) and immunology. Receptor activator of nuclear factor κB ligand (RANKL), the main regulator of osteoclastogenesis, is the primary culprit responsible for the enhanced activation of osteoclasts and inflammatory diseases, such as occurs in rheumatoid arthritis. Activated T cells directly and indirectly increase the expression of RANKL thereby promoting osteoclastic activity and excessive bone loss in inflammatory and autoimmune diseases and cancer. Indeed, there is more and more evidence that osteoporosis is associated with alterations of the immune system. Other connections have been discovered in osteoimmunology and include the importance of osteoblasts in maintenance of the hematopoietic stem cell niche, lymphocyte development, and the functions of immune cells participating in osteoblast and osteoclast development. Cytokines, chemokines, transcription factors and co-stimulatory molecules are shared by both systems. Editor’s comment: Osteoimmunology is an innovative field and more research is needed to prevent and treat the bone loss which accompanies inflammatory and autoimmune diseases. Rauner M, et al. Int Arch Allergy Immunol 2007; 143:31.

11. THE STATUS OF US ALLERGY/IMMUNOLOGY PHYSICIANS (AIP) IN THE 21ST CENTURY: A REPORT FROM THE AMERICAN ACADEMY OF ALLERGY, ASTHMA AND IMMUNOLOGY (AAAAI) WORKFORCE COMMITTEE
The AAAAI has tracked the U.S. Allergy/Immunology Physician Workforce (AIPW) for the past 30 years. The current report concludes that there is an increase in diversity, training, and that 91% of AIP are board certified. Training programs are slowly increasing and the number of graduates has increased. Patients seen are more complex and less allergen immunotherapy administered. Personal, professional and economic satisfaction of the physician has increased. Even though the number of trainees is increasing, they are not expected to replace the diminishing practitioner supply amid growing U.S. population demand. Editor’s comment: The numbers of trainees are increasing, however, they are not sufficient to meet the increased needs for future care. Marshall GD. JACI 2007; 119:802.