IntroductionTL1A (TNFSF15) augments IFN-γ production by IL-12/IL-18 responsive human T cells. Its ligand, death domain receptor 3 (DR3), is induced by activation on T and NK cells. Although IL-12/IL-18 induces DR3 expression on most NK cells, addition of TL1A minimally increases IFN-γ production.Methods51Chromium release and flow cytometric analysis were used to determine whether the TL1A-DR3 pathway is implicated in tumor cell lysis. Our aim was to determine whether the TL1A-DR3 pathway is implicated in tumor cell lysis.ResultsTL1A had no additional effect on IL-12/IL-18-induced cytotoxicity against an NK-susceptible tumor (K562); however, it promoted cytotoxicity against NK-resistant targets susceptible to lysis only by activated NK cells.DiscussionWith IL-12/IL-18 activation, TL1A increased CD107a expression on NK cells which led to enhanced lysis of Daudi by PBMC and purified NK cells. To a lesser degree, TL1A increased lysis of colorectal adenocarcinoma epithelial derived lines (WiDr and SW837) by IL-12/IL-18-activated cells.ConclusionTL1A increased cytotoxicity of IL-12/IL-18-activated NK cells against target cells dependent on NK activation for lysis and could function in vivo as a key co-activator of NK cytotoxicity.

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Most children who may benefit from stem cell transplantation lack a matched related donor. Alternative donor transplantations with an unrelated donor (URD) or a partially matched related donor (PMRD) carry an increased risk of graft-versus-host-disease (GVHD) and mortality compared with matched related donor transplantations. We hypothesized that a strategy of partial CD3 + /CD19 + depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate the risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015. Two patients (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced nonrelapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 patients (35.3%) and extensive in 8 (11.7%). Three-year overall survival (OS) was 61.8% (95% confidence interval [CI], 50.2% to 71.4%) and event-free survival (EFS) was 52.0% (95% CI, 40.3% to 62.4%). Age 15 years was associated with decreased OS (P = .05) and EFS (P = .05). Relapse was more common in children in second complete remission (P = .03). Partially CD3 +-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCT has been associated with a higher incidence of extensive chronic GVHD compared with limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study cohort despite similar overall rates of chronic GVHD. Partial T cell depletion may expand donor options for children with malignant transplantation indications lacking a matched related donor by mitigating, but not eliminating, chronic GVHD.