If your asthma is caused by cockroach stuff then Gleevec might be helping you...

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http://ajrccm.atsjournals.org/cgi/content/full/171/1/35

Original Article

Treatment of Cockroach Allergen Asthma Model with Imatinib Attenuates

Airway Responses

A. Berlin and W. Lukacs

Department of Pathology, University of Michigan Medical School, Ann

Arbor, Michigan

Correspondence and requests for reprints should be addressed to

W. Lukacs, Ph.D., University of Michigan, Pathology, 1301 St.,

Ann Arbor, MI 48109-0602. E-mail: nlukacs@...

In the present study it was determined whether a pharmacologic approach

to blocking receptor tyrosine kinase-mediated activation during allergic

airway responses could be beneficial. To examine these responses,

allergic mice were given a single oral dose of imatinib at clinically

relevant concentrations, ranging from 0.05 to 50 mg/kg, by oral gavages

just before allergen challenge. The reduction in the allergen-induced

responses was significant and centered on reducing overall inflammation

as well as pulmonary cytokine levels. In particular, the treatment of

the mice with imatinib significantly attenuated airway hyperreactivity

and peribronchial eosinophil accumulation, and significantly reduced Th2

cytokines, interleukin-4 and interleukin-13. In addition, chemokines

previously associated with allergen-induced pulmonary disease, CCL2,

CCL5, and CCL6, were significantly reduced in the lungs of the

imatinib-treated animals. Together these data demonstrate that the

pharmacologic inhibitor imatinib may provide a clinically attractive

therapy for allergic, asthmatic responses.

The identification of effective therapy for patients with

moderate-to-severe asthma has been relegated in recent years to

developing more efficient delivery of steroids to the airway (33, 34).

These nonspecific compounds decrease the production and release of a

wide array of immune/inflammatory mediators and significantly limit the

effect of the overall immune response. However, the ability to

specifically block certain critical activation pathways utilizing

signaling blockades may prove to be beneficial to alleviate long-term

chronic responses. In the present studies, on the basis of previously

published data from our laboratory and others (23-25, 27, 32), we

initiated an analysis of whether we could alleviate responses in our

preclinical model of cockroach antigen-induced asthma by blocking

receptor tyrosine kinases related to c-kit. Imatinib has been shown to

inhibit the c-kit and PDGFR activation pathways as well as arginine

kinase pathways, but not other receptor tyrosine kinase pathways

examined (18, 35). The data from the present study have been striking,

as not only was the development of AHR significantly reduced, but also

the inflammatory response was nearly abrogated. In particular, the Th2

cytokines that dominate the allergic airway responses were reduced in

the lung postchallenge. Although it is not clear which specific tyrosine

kinase pathways were altered with imatinib, these studies demonstrate

that this approach and, more importantly, this drug may provide a viable

therapeutic option for blocking certain aspects of asthmatic responses.

However, further studies also found that although AHR and inflammation

were reduced after a single treatment of allergic mice with imatinib,

neither serum IgE levels nor airway mucus expression were reduced,

indicating that not all aspects of chronic asthma are alleviated. This

latter issue will surely need to be addressed in additional studies

focused on longer term treatment with imatinib during the development of

allergic airway responses.

A striking aspect of these studies is the reduction in eosinophils

within and around the airway. Recent studies in patients with

hypereosinophilic syndrome have established a role for imatinib in the

reduction of eosinophil numbers and the associated pathophysiology of

this often devastating disease (19-21, 36-42). Although it is not

completely clear by what mechanism imatinib is operating during

hypereosinophilic syndrome, it has had an extremely beneficial effect in

a significant number of patients related to a mutation in PDRFR-{alpha}

(37, 38). The data from the present studies suggest that imatinib may

have an overall effect on the immune/inflammatory response during

antigen-specific reactions. Others and we have established that

inhibition of SCF in the airways of allergic mice can significantly

attenuate the inflammatory/immune responses (23-25, 27, 32). Previous

data suggest that the role of SCF would be multifactorial by inhibiting

not only the local mast cell populations involved early on during the

response but also the recruitment and activation of eosinophils (22, 23,

43-45). Furthermore, the recent identification of increased expression

of both SCF and c-kit in airways of individuals with asthma gives

additional support for targeting this activation pathway (28). However,

because imatinib may also have effects on other receptor tyrosine kinase

family members, such as PDGFR, the effects observed in this study likely

were an outcome of blocking other pathways as well. The responses are

also likely to encompass the alteration of bone marrow-derived cells,

especially if imatinib is given long term. We found no alteration of

circulating leukocyte numbers (data not shown), but have not performed

extensive studies to examine bone marrow or peripheral leukocyte counts

in the present studies. However, in these studies imatinib was given a

single time just before allergen challenge, and the effects may be

centered on the alleviation of the inflammatory responses directly

activated within the airways. The reduction of chemokines may have

resulted from decreased Th2 cytokines as well as the direct effects of

blocking specific signaling processes related to specific receptor

tyrosine kinase pathways.

Previous observations in patients treated with imatinib for chronic

myeloid leukemia have identified increases in IFN after a 3-month

treatment protocol, potentially suggesting an alteration of the overall

balance of Th1 and Th2 type responses (46). In contrast, another study

that examined T cell responses in patients with chronic myeloid leukemia

before and after imatinib treatment found no difference in the Th1/Th2

cytokine levels on polyclonal activation (47). Interestingly, data

suggest that imatinib may produce long-term, event-free survival in

patients with T cell lymphoid blastic phase (48). Another recent

publication has indicated that imatinib treatment affects the

development of CD34+ progenitor cells into dendritic cells (49), further

supporting a role for imatinib in altering the development of

detrimental immune responses. Related to the current study are previous

observations where SCF has been specifically blocked in the airway,

either by antibody or antisense therapy, and an alteration in Th2

cytokines observed (31, 32). Thus, by blocking the initiation of this

pathway a significant effect can be observed in the expression of a

number of allergen-induced cytokines.

These studies have identified a potential avenue of treatment that

centers on blocking certain activation pathways that have previously not

been considered for asthma therapy. These results, although striking,

deserve additional investigation within preclinical models of allergic

airway disease and possibly, subsequent investigation in populations of

patients with asthma.