No abstract

Interleukin 12 (IL‐12)‐activated NK1.1+TCRα β+ (NKT2) and NK1.1+TCRα β– (NK) cells exhibit cytotoxic activity against a wide variety of tumor cells in the absence of prior sensitization. Here we demonstrate that the integrin adhesion receptor LFA‐1 (CD11a / CD18) regulates the cytotoxic activity of IL‐12‐activated NKT and NK cells against YAC‐1 and EL‐4 tumor cells. Differentiation in vivo and the expression of the cytolytic effector molecules perforin and Fas‐L were comparable in both IL‐12‐activated NKT and NK cells from LFA‐1– / – and LFA‐1+ / + mice. However, LFA‐1– / – IL‐12‐activated NKT and NK cells showed impaired conjugate formation with target cells. These results provide the first genetic evidence for a role for an adhesion receptor in killing by IL‐12‐activated NK cells.

Bombyx mori cypovirus is a major pathogen which causes significant losses in silkworm cocoon harvests because the virus particles are embedded in micrometer-sized protein crystals called polyhedra and can remain infectious in harsh environmental conditions for years. But the remarkable stability of polyhedra can be applied on slow-release carriers of cytokines for tissue engineering. Here we show the complete healing in critical-sized bone defects by bone morphogenetic protein-2 (BMP-2) encapsulated polyhedra. Although absorbable collagen sponge (ACS) safely and effectively delivers recombinant human BMP-2 (rhBMP-2) into healing tissue, the current therapeutic regimens release rhBMP-2 at an initially high rate after which the rate declines rapidly. ACS impregnated with BMP-2 polyhedra had enough osteogenic activity to promote complete healing in critical-sized bone defects, but ACS with a high dose of rhBMP-2 showed incomplete bone healing, indicating that polyhedral microcrystals containing BMP-2 promise to advance the state of the art of bone healing.

NKT cells produce large amounts of cytokines associated with both the Th1 (IFN-γ) and Th2 (IL-4) responses following stimulation of their invariant Vα14 Ag receptor. The role of adhesion molecules in the activation of NKT cells by the Vα14 ligand α-galactosylceramide (α-GalCer) remains unclear. To address this issue, LFA-1−/− (CD11a−/−) mice were used to investigate IL-4 and IFN-γ production by NKT cells following α-GalCer stimulation. Intriguingly, LFA-1−/− mice showed increased IL-4, IL-5, and IL-13 production and polarized Th2-type responses in response to α-GalCer in vitro and in vivo. Furthermore, the Th2-specific transcription factor GATA-3 was up-regulated in α-GalCer-activated NKT cells from LFA-1−/− mice. These results provide the first genetic evidence that the adhesion receptor LFA-1 has a crucial role in Th2-polarizing functions of NKT cells.

We examine the osteogenicity of a sponge biomaterial consisting of a biodegradable mixture of gelatin and beta-tricalcium phosphate (betaTCP) that bound bone morphogenetic protein 2 (BMP-2) in critical-sized bone defects in rats. Gelatin-betaTCP sponges containing either phosphate buffered saline or incorporating BMP-2 are implanted into 5 mm diameter bone defects created in rat mandibles. We assess the defects biweekly for 8 weeks following implantation. There is significantly higher osteoinductive activity and significantly more Gla-osteocalcin content at bone-defect healing sites treated with gelatin-betaTCP sponges incorporating BMP-2 than there is in those treated with sponges that did not contain BMP-2. Histologically, new bone that contains bone marrow and that is connected to the original bone almost entirely replaces the regenerated bone. These results show that biodegradable gelatin-betaTCP incorporating BMP-2 is osteogenic enough to promote healing in large bone defects.