Similar sequence, different function
During cutaneous inflammation in humans, both hS100A7 (psoriasin) and hS100A15 are upregulated. Despite a very recent evolutionary divergence and an extremely high homology (93% sequence identity), these proteins not only exhibit unique expression but also have distinct functions. Wolf and colleagues demonstrated that in vitro hS100A15 was chemotactic for granulocytes and monocytes but not for lymphocytes, whereas hS100A7 was chemotactic for all three types of leukocytes. Another interesting difference between these two similar proteins is the receptor involved in chemotaxis: hS100A15 signals through a Gi protein–coupled receptor (GiPCR), whereas hS100A7 appears to function through the receptor for advanced glycation end products. These two proteins are proinflammatory and function synergistically in vivo, albeit through unique molecular mechanisms. Understanding this diversity coupled with this synergy will undoubtedly facilitate the development of therapies for cutaneous inflammatory diseases such as psoriasis. (J Immunol 181:1499–506, 2008)
Improved adjuvant for melanoma
IFN-
2b has been shown to reduce the risk of recurrence or death in patients with stage IIb and stage III melanoma. Because these patients are at high risk for tumor recurrence following surgery, effective adjuvant therapy is particularly useful. Pegylation of IFN-2b has been proven safe for use in several types of cancer. Eggermont and colleagues recently demonstrated that recurrence-free survival was significantly improved in patients with stage III melanoma who received adjuvant IFN-2b and that an increase in metastasis-free survival was observed, although the difference was not statistically significant. The toxicity of this treatment was also considered acceptable. Pegylated IFN-2b may be an effective option for adjuvant treatment to reduce the risk of relapse and potentially achieve a cure. Although these results indicate that patients with low tumor volume and an ulcerated primary tumor may be likely candidates to benefit from adjuvant IFN-2b, this study highlights the importance of confirming markers in such patients. (Lancet 372:117–26, 2008)
Direct delivery
Integrin-v
3, which is preferentially expressed on angiogenic endothelium in malignant tissues, is an attractive target for the delivery of cancer therapeutics via nanoparticles (NPs). Previous work indicated that the v-integrin-targeting peptide RGD-4C was effective at delivering doxorubicin (Dox) to tumor neovasculature. Murphy and colleagues then demonstrated that integrin-v3 targeting of Dox-containing NPs strongly inhibited angiogenesis. After RGD-Dox-NP treatment in both pancreatic carcinoma and renal cell carcinoma models, a modest effect was observed on primary tumor growth and a substantial effect was observed on metastatic disease. Importantly, a 15-fold improvement in drug efficacy was noted when Dox was delivered via this integrin-targeting system. Because targeted NP delivery exhibited high efficiency without accompanying side effects, this targeting will be a candidate mechanism for the delivery of new pharmacological agents designed to suppress tumor or vascular cell signaling. (Proc Natl Acad Sci USA 105:9343–8, 2008)
TH17 cells: of mice and men
TH17 cells have been implicated in an array of autoimmune disorders, from multiple sclerosis to rheumatoid arthritis and psoriasis. In vitro studies on the differentiation of TH17 cells have illuminated differences between mice and humans. Using a system to independently examine the effects of cytokines on memory T cells and naive CD4+ lymphocytes from humans, Yang and colleagues demonstrated a requirement for IL-21 and transforming growth factor (TGF)- in differentiation of naive CD4+ T cells to TH17 cells. In addition, IL-1 and IL-6 induced IL-17A secretion from human memory CD4+ T cells. Induction of the critical transcription factors RORC2 and FOXP3 was similar in mouse and human naive CD4 cells; however, induction of IL-17A by IL-6 and TGF- differed between the species. This report more clearly defines the conditions required for human TH17-cell differentiation and offers insight into future exploration of human inflammatory TH17 responses in autoimmune diseases. (Nature 454:350–2, 2008)
CD19 is critical in systemic sclerosis
Systemic sclerosis (SSc) is a connective tissue disease characterized by excessive extracellular matrix deposition, abnormal activation of immune cells, elevated serum cytokine levels, and the presence of autoantibodies. The recent development of a new bleomycin-induced SSc model prompted Yoshizaki and colleagues to examine this disease in mice deficient for CD19, a critical signal-transduction component that regulates humoral immune responses, autoimmunity, and cytokine production. Interestingly, CD19 deficiency inhibited the development of skin and lung fibrosis and autoantibody production following induction of SSc with bleomycin. Bleomycin treatment enhanced the production of hyaluronan, a Toll-like receptor (TLR2 and TLR4) ligand that stimulated B cells to generate cytokines. In the absence of CD19, however, this bleomycin-induced cytokine production was suppressed. Importantly, the reduced fibrosis in the CD19-deficient mice was accompanied by decreased infiltration of immune cells, and thus the authors asserted the importance of B-cell activation for downstream inflammation and autoimmune response in SSc. (Am J Pathol 172:1650–63, 2008)
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