Trent and colleagues, in their original study of heart failure in patients receiving imatinib, discuss the retrospective nature of similar studies and the difficulty of attributing symptoms of heart failure to the drug. 1 The symptoms of heart failure, including edema and pleural effusion, can also result from T-cell abnormalities with the tyrosine kinase inhibitors. Peripheral edema can arise from a T-helper-1 (Th1) cell-mediated hypersensitive reaction, whereas pleural effusions and pulmonary involvement are known to be T-cell-mediated. 2 In support of the latter, a series of 40 patients on dasatinib yielded 6 individuals who developed pleural effusions and lung involvement with lymphocytic infiltration, rather than cardiac impairment. 3 If edema and pulmonary involvement develop secondary to T-cell abnormalities, withholding the drug until symptoms resolve, followed by gradual reintroduction at lower doses, is preferable to attributing these adverse effects to ''drug-induced cardiac toxicity''. 3 The importance of imatinib to T-cell responses has been studied. However, its effects on the balance between the Th1 and Th2 clones are likely as important. 4 Although the cytokines elaborated by either of these clones can serve as autocrine growth factors, they also regulate the development and differentiation of each other. 5 For this reason, edema or pleural effusion in certain individuals may be explained by the balance of Th1 to Th2 suppression by imatinib. Relative excess of the former causes adverse effects, whereas the latter can be beneficial in autoimmune disorders. Individuals with autoimmune disorders with a higher Th2:Th1 ratio are suitable candidates for imatinib for similar reasons. Thus, it is important to dissect the adverse effects of imatinib into those related to T-cell and heart abnormalities , so that an effective drug is not withheld. REFERENCES 1. Trent JC, Patel SS, Zhang J, et al. Rare incidence of conges-tive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate. Cancer. 2010; 116:184-192. 2. Li L, Elliott JF, Mosmann TR. IL-10 inhibits cytokine production , vascular leakage, and swelling during T-helper-1 cell-induced delayed-type hypersensitivity. J Immunol. 1994;153: 3967-3978. 3. Bergeron A, Réa D, Levy V, et al. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia. Am J Respir CritCareMed. 2007;176:814-818. 4. Seggewiss R, Price DA, Purbhoo MA. Immunomodulatory effects of imatinib and second generation tyrosine kinase inhibitors on T cells and dendritic cells. Concerning our recent article, 1 the comments by Dr. Jecko are thought-provoking and well-received. Dr. Jecko poignantly and rationally postulates a mechanism by which tyrosine kinase inhibitors modulate T-cell function , resulting in pleural effusions and edema. Imatinib-associated edema and pleural effusions are a common detriment to patient quality of life, and the pathophysiology remains unknown. Therefore, rigorous evaluation of alternate potential mechani...

A multitude of leukocyte migration events is needed to accomplish immunosurveillance in vertebrate organisms. Blood monocytes derived from central hematopoietic organs continuously seed the periphery with sentinels specialized in antigen uptake. Antigen encounter results in the mobilization of antigen-presenting cells (APC) to afferent lymphatics and their recruitment to secondary lymphoid organs, where they trigger T-cell responses. Long-distance migration of leukocytes is accomplished via blood and lymph circulation and thus requires transendothelial migration through vessel walls. The interaction of leukocytes with vascular endothelial cells during extravasation at sites of inflammation is a highly regulated process. After an initial, predominantly selectin-mediated "rolling" step, engagement of G-protein-coupled chemokine receptors leads to activation of integrins and the establishment of firm arrest, followed by diapedesis (2, 3).Recently a novel chemokine named fractalkine (FKN) (neurotactin [NTN]) was identified (1, 15) and shown to have unique properties. FKN has a CX 3 C chemokine domain and thus constitutes, according to the current chemokine nomenclature based on the spacing of N-terminal cysteines, its own CX 3 C family. Unlike any other known chemokine, the CX 3 C module was found to exist in two isoforms; one is membrane anchored and presented on an extended mucin-like stalk, and the other is a soluble form resulting from membrane-proximal proteolytic cleavage of FKN. In addition to its classical function as a chemoattractant, high-affinity interaction of FKN with its specific receptor CX 3 CR1 (8) mediates leukocyte arrest under flow conditions (4). In vitro data show that this firm adhesion is signaling independent and does not involve integrin activation, and may thus represent a novel mechanism in leukocyte trafficking (4, 7). FKN has been shown to be expressed on activated endothelial cells (1, 15), dendritic cells (DC) (9, 16), and neurons (6, 14). The FKN receptor, CX 3 CR1 (formerly V28 [18]), is a typical seven-transmembrane G-protein-coupled receptor. CX 3 CR1 is expressed on human monocytes and undefined subsets of NK and T cells (8). Expression of FKN and CX 3 CR1 in neurons and microglia, respectively, has fostered speculations that the receptor-ligand pair might be crucial for neuronal-glial cross talk (6,14).To investigate the in vivo role of FKN-CX3CR1 interactions, we generated a mouse mutant that lacks the FKN receptor. Our strategy was to replace the murine CX 3 CR1 gene with the gene encoding the enhanced green fluorescent protein (EGFP; Clontech). This approach allowed not only the generation of a mutant CX 3 CR1 locus but also the examination of the CX 3 CR1 expression pattern and migration of cells that normally express this receptor. MATERIALS AND METHODSMolecular cloning and generation of CX 3 CR1 mutant mice. Genomic fragments of the murine CX 3 CR1 locus were isolated from a 129/Sv phage library (Stratagene, La Jolla, Calif.) by hybridization with a human CX 3 CR1 cDNA pr...

Type I interferons (IFNs) have diverse effects on innate and adaptive immune cells during infection with viruses, bacteria, parasites and fungi, directly and/or indirectly through the induction of other mediators. Type I IFNs are important for host defence against viruses. However, recently, they have been shown to cause immunopathology in some acute viral infections, such as influenza virus infection. Conversely, they can lead to immunosuppression during chronic viral infections, such as lymphocytic choriomeningitis virus infection. During bacterial infections, low levels of type I IFNs may be required at an early stage, to initiate cell-mediated immune responses. High concentrations of type I IFNs may block B cell responses or lead to the production of immunosuppressive molecules, and such concentrations also reduce the responsiveness of macrophages to activation by IFNγ, as has been shown for infections with Listeria monocytogenes and Mycobacterium tuberculosis. Recent studies in experimental models of tuberculosis have demonstrated that prostaglandin E2 and interleukin-1 inhibit type I IFN expression and its downstream effects, demonstrating that a cross-regulatory network of cytokines operates during infectious diseases to provide protection with minimum damage to the host.