Trends in Immunology
Volume 33, Issue 12, December 2012, Pages 613-625
Journal home page for Trends in Immunology

Review
New models for analyzing mast cell functions in vivo

https://doi.org/10.1016/j.it.2012.09.008Get rights and content

In addition to their well-accepted role as critical effector cells in anaphylaxis and other acute IgE-mediated allergic reactions, mast cells (MCs) have been implicated in a wide variety of processes that contribute to disease or help to maintain health. Although some of these roles were first suggested by analyses of MC products or functions in vitro, it is critical to determine whether, and under which circumstances, such potential roles actually can be performed by MCs in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products during biological responses in vivo, and comments on some of the similarities and differences in the results obtained with these newer versus older models of MC deficiency.

Section snippets

The spectrum of potential MC functions: an embarrassment of riches

Trying to figure out what MCs do in vivo has been challenging. This is not for want of hypotheses. Indeed, given what has been reported about MCs based on in vitro or in vivo evidence, the possibilities appear to be almost endless (Box 1). Taking such information into account, one can come up with a nearly limitless list of potential or possible MC functions – spanning many if not all aspects of health, host defense, and disease. But what, in fact, are the important functions of MCs in vivo,

Kit mutant MC-deficient mice and ‘MC knock-in mice’

To date, mice whose sole abnormality is a specific lack of all populations of MCs have not been reported. However, we and others have used mice with abnormalities affecting KIT, the receptor for the main MC growth and survival factor, stem cell factor (SCF) 2, 3 (which sometimes are collectively called kit mutant mice) to analyze the functions of MCs in vivo 4, 5, 6, 7, 8. The two types of MC-deficient mice used most commonly for such studies are WBB6F1-KitW/W-v and C57BL/6-KitW-sh/W-sh mice 5,

Mutant mice with constitutive MC deficiency unrelated to c-kit abnormalities

KIT has pleiotropic functions unrelated to MCs (Box 3). Therefore, even when MC engraftment results in MC numbers and anatomical distributions in the recipient kit mutant mice that are very similar to those of the corresponding WT mice, it is possible that such adoptively transferred MCs can normalize some of the biological responses that are abnormal in kit mutant mice, because the transferred MCs compensate in the mutant mice for abnormalities in lineages other than the MC, abnormalities that

Inducible depletion of MCs

Using mouse models to test the hypothesis that MCs represent an important therapeutic target in a particular setting should ideally be performed using mice in which inducible and selective MC ablation can be achieved. Depletion of MCs from mice by conventional techniques, such as the injection of depleting antibodies, is limited by the lack of surface markers that have been shown to be unique to the MC population. For example, repeated treatment with antibodies that neutralize SCF [45] or block

Mutant mice with deletion of MC-associated products

If a mediator is selectively expressed by MCs (to prove this, expression needs to be analyzed in other cell types under both baseline and pathological conditions), its role can be investigated in vivo by testing animals in which that mediator has been knocked out. However, many of these highly MC-associated (if not truly MC-selective) mediators (such as MC-associated proteases) show strong interdependence in terms of proper storage in the cytoplasmic granules and this clearly must be kept in

Kit mutant versus KIT-independent MC-deficient mice in models of host defense and disease: concordance, controversies, and opportunities

As reviewed above, individual mouse models of MC deficiency, or models to alter the expression of MC-associated products, differ in their features and may vary in their advantages and limitations for studies of MC function. The newer models of MC deficiency are particularly attractive because they lack the KIT-related phenotypic alterations associated with kit mutant MC-deficient mice. However, because the newer models only recently have been described, it is likely that there is still more to

Concluding remarks

This is an exciting time in MC research. The continued availability of old models (including MC knock-in kit mutant mice and various MC protease-deficient mice), combined with the introduction of several promising new models of MC deficiency or for MC-targeted deletion of MC products, offers a wealth of opportunities to enhance progress in solving the long-standing ‘riddle of the mast cell’, at least in mice. Some of this work may even suggest new approaches for the treatment of diseases in

Acknowledgments

We thank the members of the Galli laboratory and our collaborators and colleagues for their contributions to some of the work reviewed herein and we apologize to the many contributors to this field whose work was not cited because of space limitations. We also thank Dr Mindy Tsai for critical reading of the manuscript. L.L.R. is the recipient of fellowships from the French “Fondation pour la Recherche Médicale FRM” and the Stanford Pediatric Research Fund and is funded by grant #SPO106496 from

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    These authors contributed equally to this work.

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