Page 366 - Clinical Immunology_ Principles and Practice ( PDFDrive )

346 ParT TwO Host Defense Mechanisms and Inflammation

appropriate intake of calcium and vitamin D. Interferon-α There is a great need for better understanding of molecular
(IFN-α) has been reported to be helpful as a second-line agent mechanisms of mast cell–related human diseases for improved
in refractory disease. 52 diagnosis and treatment in the long term. For most atopic diseases
Cytoreductive therapy has a role in the treatment of aggressive and for mastocytosis, the current standard of care consists of
systemic mastocytosis (ASM) and mast cell leukemia, although avoidance of triggers and symptomatic therapies aimed at media-
59
data from large clinical trials are lacking. Imatinib, a tyrosine tor blockade. Drugs that safely and selectively suppress the
kinase inhibitor, has been effective in reducing mast cell burden pathogenic functions of mast cells could substantially improve
in only a small subset of patients who lack the D816V mutation quality of life in patients suffering from common conditions,
in KIT. Although clinical responses to other tyrosine kinase such as asthma, as well as rare ones, such as mastocytosis. At
52
inhibitors have been largely disappointing, a very recent trial the same time, the critical functions for mast cells in innate
of midostaurin, which is active on D816V, showed substantial immunity identified in mouse models require investigation in
55
promise in patients with advanced SM. More studies are needed humans. Whether mast cell effector functions can be selectively
to determine those patients most likely to benefit. exploited to enhance immune responses and vaccine efficacy is
Additional treatment of patients with SM and associated clonal an area of active investigation.
hematological non–mast cell lineage disease (AHNMD) depends
on the associated hematological disorder. The general approach Please check your eBook at https://expertconsult.inkling.com/
is to treat AHNMD as if SM were not present and to treat the for self-assessment questions. See inside cover for registration
SM as if the AHNMD were not present, while closely monitoring details.
patients for mast cell activation symptoms during therapy. 56
Prognosis REFERENCES
Each category of mastocytosis carries a different prognosis. 1. Voehringer D. Protective and pathological roles of mast cells and
Pediatric patients with CM have complete resolution by adulthood basophils. Nat Rev Immunol 2013;13(5):362–75.
in the majority of cases. Patients with indolent systemic masto- 2. Arinobu Y, Iwasaki H, Gurish MF, et al. Developmental checkpoints of
cytosis (ISM) generally have a normal life expectancy, and ISM the basophil/mast cell lineages in adult murine hematopoiesis. Proc Natl
rarely evolves into more aggressive categories. However, median Acad Sci USA 2005;102:18105–10.
survival in other forms of SM is diminished (24 months in 3. Siracusa MC, Kim BS, Spergel JM, et al. Basophils and allergic
inflammation. J Allergy Clin Immunol 2013;132:789–801.
SM-AHNMD, 48 months in ASM). Mast cell leukemia is the 4. Dahlin JS, Malinovschi A, Öhrvik H, et al. Lin- CD34hi CD117int/hi
rarest and most severe form of mast cell disease, with median FcεRI + cells in human blood constitute a rare population of mast cell
survival of only 2 months. 57 progenitors. Blood 2016;127:383–91.
5. Dwyer DF, Barrett NA, Austen KF, et al. Expression profiling of
SUMMARY AND FUTURE RESEARCH DIRECTIONS constitutive mast cells reveals a unique identity within the immune
system. Nat Immunol 2016;17:878–87.
6. Akin C. Clonality and molecular pathogenesis of mastocytosis. Acta
Haematol 2005;114:61–9.
ON THE HOrIZON 7. Han NR, Oh HA, Nam SY, et al. TSLP induces mast cell development and
aggravates allergic reactions through the activation of MDM2 and STAT6.
• Newer mouse models of mast cell deficiency and of inducible basophil J Invest Dermatol 2014;134:2521–30.
deficiency will help: 8. Lantz CS, Boesiger J, Song CH, et al. Role for interleukin-3 in mast-cell
• Clarify the role of mast cells in normal physiology and basophil development and in immunity to parasites. Nature
• Improve understanding of the role of mast cells in atopic and 1998;392:90–3.
nonatopic diseases 9. Godfraind C, Louahed J, Faulkner H, et al. Intraepithelial infiltration by
• Translational research will help: mast cells with both connective tissue-type and mucosal-type
• Improve understanding of the mechanisms of mast cell- and characteristics in gut, trachea, and kidneys of IL-9 transgenic mice. J
basophil-mediated diseases Immunol 1998;160:3989–96.
• Identify additional mutations in c-KIT and other genes that are 10. Yanagida M, Fukamachi H, Ohgami K, et al. Effects of T-helper 2-type
associated with mastocytosis cytokines, interleukin-3 (IL-3), IL-4, IL-5, and IL-6 on the survival of
• Clinical research is needed: cultured human mast cells. Blood 1995;86:3705–14.
• To improve diagnostic tools for atopic diseases and mast cell 11. Hsieh FH, Lam BK, Penrose JF, et al. T helper cell type 2 cytokines
disorders
• To improve treatment of and eventually cure asthma and atopic coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene
diseases production by human cord blood-derived mast cells: profound induction
• To improve treatment of and eventually cure mastocytosis of leukotriene C(4) synthase expression by interleukin 4. J Exp Med
2001;193:123–33.
12. Gurish MF, Boyce JA. Mast cells: ontogeny, homing, and recruitment
of a unique innate effector cell. J Allergy Clin Immunol
The mouse models that have been classically used to study mast 2006;117:1285–91.
cell functions are based upon Kit mutations that result in other 13. Ochi H, Hirani WM, Yuan Q, et al. T helper cell type 2
defects besides a lack of mast cells. Newer transgenic models of cytokine-mediated comitogenic responses and CCR3 expression
mast cell deficiency have been developed in recent years and will during differentiation of human mast cells in vitro. J Exp Med
1999;190:267–80.
help clarify mast cell roles in both normal physiology and in 14. Brightling CE, Ammit AJ, Kaur D, et al. The CXCL10/CXCR3 axis
disease processes by avoiding these confounding factors. Mouse mediates human lung mast cell migration to asthmatic airway smooth
models of inducible basophil deficiency have recently been muscle. Am J Respir Crit Care Med 2005;171:1103–8.
developed and will be important in improving our understanding 15. Kanakura Y, Sonoda S, Nakano T, et al. Formation of mast-cell colonies
of basophil functions. 58 in methylcellulose by mouse skin cells and development of mucosal-like