Summary Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for chronic myeloid leukemia (CML) patients. Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead “switch-control” inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1T315I-expressing cell lines, prolongs survival in mouse models of T315I-mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph+ leukemia.

Toxoplasma gondii is an opportunistic intracellular parasite which induces a highly strong type 1 cytokine response. The present study focuses on defining the factors influencing the outcome of infection with tachyzoites of the type I, highly lethal RH strain, relative to the type II, low virulence strain ME49. Infection with the RH strain led to widespread parasite dissemination and rapid death of mice; in contrast, mice survived low virulence strain ME49 infection, and tachyzoite dissemination was much less extensive. Furthermore, massive apoptosis and disintegration of the splenic architecture was characteristic of RH, but not ME49, infection. In addition, hyperinduction of IFN-γ and lack of NO production were found during RH, in contrast to ME49 infection. These data demonstrate that Toxoplasma strain characteristics exert a profound effect on the host immune response and that the latter itself is a crucial determinant in parasite virulence.

The immunomodulatory role of neutrophils during infection with Toxoplasma gondii was investigated. Monoclonal antibody-mediated depletion revealed that neutrophils are essential for survival during the first few days of infection. Moreover, neutrophil depletion was associated with a weaker type 1 immune response as measured by decreased levels of gamma interferon, interleukin-12 (IL-12) and tumor necrosis factor alpha. IL-10 was also decreased in depleted animals. Additionally, splenic populations of CD4 ؉ T cells, CD8 ؉ T cells, and NK1.1 ؉ cells were decreased in depleted mice. Neutrophil-depleted mice exhibited lesions of greater severity in tissues examined and a greater parasite burden as determined by histopathology and reverse transcription-PCR. We conclude that neutrophils are critical near the time of infection because they influence the character of the immune response and control tachyzoite replication.The immune system is a complex nonlinear system, involving the coordination of multiple cell types. Disease often results from an insufficient immune response. Lack of protection can occur when any one or more of the components of the immune system are impaired. Neutropenia is a risk factor associated with Aspergillus fumigatus, Candida albicans, Strongyloides ratti, Yersinia enterocolitica, Chlamydia trachomatis, Mycobacterium tuberculosis, Listeria monocytogenes, and Toxoplasma gondii infections (2,3,5,7,8,22,27,31,41). In some cases, neutropenia has been correlated with impaired protective acquired immunity, suggesting that neutrophils function as immunomodulators of acquired immunity (27, 31). The list of microbes affected by the actions of neutrophils is ever-growing, and it is evident that these cells are involved in the immune response to a highly diverse array of both intracellular and extracellular pathogens.We examined the development of immunity during T. gondii infection in mice depleted of neutrophils by monoclonal antibody (MAb) administration. T. gondii is an obligate intracellular protozoan parasite that poses an important public health risk. Congenital infections may result in severe birth defects, and reactivation of chronic infection can lead to development of encephalitis, a particular problem for persons who are immunosuppressed (25, 28). We found that neutrophil depletion at the time of infection led to development of lesions in multiple organs, including the spleen, lung, liver, and brain, and was associated with an impaired ability to produce early gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣) and interleukin-12 (IL-12). Splenic populations of T cells and NK cells were decreased in neutrophil-depleted infected mice. Moreover, neutrophil-depleted mice harbored an increased parasite burden. We conclude that neutrophils are important immunomodulators early in the course of T. gondii infection and play a critical role in protecting the host from uncontrolled tachyzoite replication. MATERIALS AND METHODSMice. C57BL/6 female mice (6 to 12 weeks of age) were obtained fro...

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