The results indicated that adoptive immunotherapy using in vitro-activated autologous gammadelta T cells was well tolerated and induced anti-tumor effects.

Human Vγ2 Vδ2-bearing T cells have recently received much attention in cancer immunotherapy. In this study, we conducted a phase I/II clinical trial of the adoptive transfer of γδ T cells to patients with advanced renal cell carcinoma. Eleven patients who had undergone nephrectomy and had lung metastasis were enrolled. Peripheral blood γδ T cells obtained from the patients were stimulated ex vivo with 2-methyl-3-butenyl-1-pyrophosphate (2M3B1PP), a synthetic pyrophosphomonoester antigen, and transferred in combination with zoledronic acid (Zol) and teceleukin (recombinant human interleukin-2). Expanded γδ T cells exhibited potent cytotoxic activity against tumor cells in vitro, and the proportion of peripheral blood γδ T cells among CD3(+) cells typically peaked three to 5 days after transfer. Tumor doubling time was prolonged in all 11 patients, and the best overall responses were 1 CR, 5 SD, and 5 PD, as defined based on Response Evaluation Criteria in Solid Tumors (RECIST). Although ten patients developed adverse reactions of grade ≥3, they were likely to have been the result of the concomitant infusion of Zol and IL-2, and most symptoms swiftly reverted to normal during the course of treatment. In conclusion, this clinical trial demonstrated that our regimen for the adoptive transfer of γδ T cells in combination with Zol and IL-2 was well tolerated and that objective clinical responses could be achieved in some patients with advanced renal cell carcinoma.

Programmed cell death-1 (PD-1) is an inhibitory receptor and plays an important role in the regulation of ab T cells. Little is known, however, about the role of PD-1 in cd T cells. In this study, we investigated the expression and function of PD-1 in human cd T cells. Expression of PD-1 was rapidly induced in primary cd T cells following antigenic stimulation, and the PD-1 1 cd T cells produced IL-2. When PD-1 1 cd T cells were stimulated with Daudi cells with and without programmed cell death ligand-1 (PD-L1) expression, the levels of IFN-c production and cytotoxicity in response to PD-L1 1 Daudi cells were diminished compared to the levels seen in response to PD-L1 À Daudi cells. The attenuated effector functions were reversed by anti-PD-L1 mAb. When PD-1 1 cd T cells were challenged by PD-L1 1 tumors pretreated with zoledronate (Zol), which induced cd TCR-mediated signaling, the resulting reduction in cytokine production was only slight to moderate compared to the reduction seen when PD-1 1 cd T cells were challenged by PD-L1 À tumors. In addition, cytotoxic activity of PD-1 1 cd T cells against Zol-treated PD-L1 1 tumors was comparable to that against Zol-treated PD-L1 À tumors. These results suggest that TCR triggering may partially overcome the inhibitory effect of PD-1 in cd T cells.Keywords: cd T cells . Phosphoantigen . PD-1 . PD-L1 . Tumor Supporting Information available online IntroductionHuman Vg2Jg1.2Vd2 (also termed Vg9JPVd2)-bearing gd T cells recognize the so-called phosphoantigens, a group consisting of isopentenyl pyrophosphate (IPP) and related metabolites derived from microbial pathogens in a gd TCR-dependent manner [1][2][3][4]. One of the most potent naturally occurring phosphoantigens is (E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMB-PP), which is derived from the 2-C-methy-D-erythritol-4-phosphate/ 1-deoxy-D-xylulose-5-phosphate pathway, an isoprenoid-biosynthetic pathway unique to certain microbes and plants [5,6]; we and others have previously reported that the subset of gd T cells [7,8]. A growing body of evidence shows that N-BPs inhibit farnesyl pyrophosphate synthase downstream of IPP in the mammalian mevalonate pathway [9,10]. It has been suggested that the resulting intracellular accumulation of IPP in the tumor cells allows gd T cells to recognize the tumor cells [11,12], although the exact mechanisms whereby this may occur remain to be identified. An increase in intracellular IPP may also occur spontaneously in certain tumor cells [13,14]. Based on these results, it has been proposed that gd T cells may be involved in surveillance for cellular metabolic stress [15,16]. Activated gd T cells produce various cytokines including IFN-g and TNF-a and also exhibit potent cytotoxic activity [17,18], and thus may serve as potential effector cells against tumors [19]. The membrane protein known as programmed cell death-1 (PD-1) is a member of the immunoglobulin superfamily, which is induced in ab T cells following antigenic stimulation [20]. Upon engagement with its specific ligan...

The use of chemokine antagonism as a strategy to inhibit leukocyte trafficking into inflammatory sites requires identification of the dominant chemokines mediating recruitment. The chemokine(s) directing T cells into cardiac allografts during acute rejection remain(s) unidentified. The role of the CXC chemokines IFN-γ inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig) in acute rejection of A/J (H-2a) cardiac grafts by C57BL/6 (H-2b) recipients was tested. Intra-allograft expression of Mig was observed at day 2 posttransplant and increased to the time of rejection at day 7 posttransplant. IP-10 mRNA and protein production were 2.5- to 8-fold lower than Mig. Whereas allografts were rejected at day 7–9 in control recipients, treatment with rabbit antiserum to Mig, but not to IP-10, prolonged allograft survival up to day 19 posttransplant. At day 7 posttransplant, allografts from Mig antiserum-treated recipients had marked reduction in T cell infiltration. At the time of rejection in Mig antiserum-treated recipients (i.e., days 17–19), intra-allograft expression of macrophage-inflammatory protein-1α, -1β, and their ligand CCR5 was high, whereas expression of CXCR3, the Mig receptor, was virtually absent. Mig was produced by the allograft endothelium as well as by recipient allograft-infiltrating macrophages and neutrophils, indicating the synergistic interactions between innate and adaptive immune compartments during acute rejection. Collectively, these results indicate that Mig is a dominant recruiting factor for alloantigen-primed T cells into cardiac allografts during acute rejection. Although Mig antagonism delays acute heart allograft rejection, the results also suggest that the alloimmune response circumvents Mig antagonism through alternative mechanisms.

A synthetic polymer gel–based insulin delivery device provides an artificial pancreas–like function in healthy and diabetic mice.