Increased natural killer T‐like cells are a major source of pro‐inflammatory cytokines and granzymes in lung transplant recipients

Abstract

Current therapeutics is inadequate at suppressing NKT-like cell numbers and their production of pro-inflammatory mediators known to be associated with graft rejection. Alternative therapies that specifically target NKT-like cells may improve patient morbidity.

Bronchiolitis obliterans syndrome is associated with increased peripheral blood natural killer and natural killer T-like granzymes, perforin, and T-helper-type 1 pro-inflammatory cytokines

“…14 We previously showed lack of modulation of granzyme B in T, NK, and NKT-like cells in the presence of therapeutic doses of cyclosporine, tacrolimus, or prednisolone, suggesting other strategies are necessary to reduce these cytotoxic molecules. 5 In this regard, we recently showed inhibition of T-cell granzyme B production in the presence of gabexate mesylate in vitro, and this compound may also be a suitable therapeutic agent to reduce granzyme B production by NKT-like cells and possibly NK cells. 3 Further, inhibition of pro-inflammatory cytokines in vitro was more effective for patient's T-cells than NKT-like cells, suggesting possible resistance of NKT-like cells to therapy.…”

“…3 Further, inhibition of pro-inflammatory cytokines in vitro was more effective for patient's T-cells than NKT-like cells, suggesting possible resistance of NKT-like cells to therapy. 5 Interestingly, inhibition of IFN-␥ and TNF-␣ by NK cells in blood from stable patients was more effective using these therapeutic agents than T or NKT-like cells, and future experiments are planned to investigate possible drug resistance by NK cells in patients with BOS.…”

“…5 NK cells are important in the innate immune response, also produce these pro-inflammatory mediators, and thus may also play an important role in transplant rejection. 6 Few studies have investigated the role of NK cells in lung transplant rejection.…”

Up-regulation of alternate co-stimulatory molecules on proinflammatory CD28null T cells in bronchiolitis obliterans syndrome

“…One hundred and fifty microlitres of peripheral blood were stained with monoclonal antibodies as reported previously to CD8 fluorescein isothiocyanate (FITC) (BD Biosciences (BD), Sydney, Australia), CD4 phycoerythrin (PE) (BD), CD3 peridinin chlorophyll-cyanine 5·5 (PerCP-Cy5·5) (BD), CD28 PE-Cy7 (BD) and CD45V450 (BD) and analysed as reported previously [8,10,13].…”

“…Down-regulation of CD28 expression following persistent antigenic stimulation has also been shown to be associated with up-regulation of CD57 expression, a terminally sulphated carbohydrate determinant found on subsets of natural killer (NK) cells and NK T-like cells associated with ageing [9]. Interestingly, we have shown recently that there are increased peripheral blood CD56 + CD3 + NK T-like cells in blood from stable lung transplant patients and that these cells exhibit increased production of proinflammatory cytokines interferon (IFN)-g and tumour necrosis factor (TNF)-a and expression of cytotoxic molecules, perforin and granzymes [10]. We hypothesized that dysregulated expression of T cell co-stimulatory molecules may be associated with steroid resistance and BOS, and identify potential new therapeutic targets that are needed urgently to improve the morbidity and mortality rates following lung transplantation.…”