Suppressive effects of vitamin C-treated induced-regulatory T cells on heart allograft rejection under vitamin C-deficient or -sufficient conditions.

Foxp3 stability of vitamin C-treated induced-regulatory T cells (V-iTregs) is superior to that of conventional iTregs (C-iTregs). However, the role of V-iTregs in allograft rejection under vitamin C-deficient conditions, such as those seen in humans, remains unclear. We aimed to elucidate the role of vitamin C treatment on generation and maintenance of iTregs from gulo knockout (Gulo-KO) mice as well as wild type (WT) mice, and in vitro and in vivo suppressive effects of V-iTregs on heart allograft rejection in either Gulo-KO or WT recipient mice. Conversion efficiency of iTregs was similar between C- and V-iTregs in both WT and Gulo-KO mice. V-iTregs from WT or Gulo-KO mice showed better in vitro Foxp3 stability than C-iTregs, although there was no difference between WT V-iTregs and Gulo-KO V-iTregs. Furthermore, V-iTregs from WT or Gulo-KO mice suppressed in vitro T cell proliferation better than C-iTregs. Heterotrophic heart transplantation from BALB/c mice to WT or vitamin C-deficient Gulo-KO C57BL/6J mice was performed following adoptive transfer of C- or V-iTregs. V-iTregs as well as C-iTregs prolonged heart allograft survival in WT and Gulo-KO mice. However, there was no difference between the C- and V-iTreg groups. Supplementation of low- or high-dose vitamin C did not induce significant changes in heart allograft survival in Gulo-KO recipients that had received V-iTregs. In conclusion, V-iTregs do not exert better suppressive effects on heart allograft survival than C-iTregs in either WT or vitamin C-deficient recipients.

Imlifidase: First Approval.

Imlifidase (IdefirixTM), a cysteine protease derived from the immunoglobulin G (IgG)­degrading enzyme of Streptococcus (S.) pyogenes is being developed by Hansa Biopharma AB for treatment of transplant rejection and rare IgG-mediated autoimmune conditions. In August 2020, intravenous imlifidase received its first global approval in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor. Imlifidase is currently undergoing clinical evaluation for the prevention of kidney transplant rejection in the USA, Australia, France and Austria, and clinical development is underway for anti-glomerular basement membrane disease, and for Guillain-Barre syndrome in France, the UK and the Netherlands. This article summarizes the milestones in the development of imlifidase leading to this first approval for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor.

Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply.

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.

Protocol-based nurse coordinator management of ambulatory tacrolimus dosing in de novo renal transplant recipients-A single-center experience with a large African American population.

INTRODUCTION: Transplant nurse (RN) coordinators review tacrolimus levels frequently and would be capable of making dose adjustments autonomously if not limited by their license. Collaborative practice agreements could be an answer; thus, the aim of this evaluation was to determine if an RN-driven protocol could be used safely and effectively to manage tacrolimus in ambulatory kidney transplant (KTX) recipients. METHODS: This was a retrospective review of all solitary adult KTX recipients between August 1, 2016, and July 29, 2017. The primary objective was to evaluate protocol adherence and frequency of use, and secondary objectives were to evaluate the utility of the protocol both overall and based on ethnicity. RESULTS: A total of 173 patients were included in the evaluation (59% African American [AA], 41% non-African American [non-AA). RN coordinators followed the protocol for 75% of tacrolimus adjustments; however, they only responded to 27% of the overall levels. There was no difference in 180-day tacrolimus-associated readmission (15% AA vs 5% non-AA, P = .06), biopsy-proven acute rejection (4% AA vs 7% non-AA, P = .363), or hyperkalemia (34% AA vs 32% non-AA, P = .87) between groups. CONCLUSIONS: Transplant nurse coordinators are capable of accurately following a protocol for tacrolimus dosage adjustment in a large, racially diverse kidney transplant center.

Assessment of treatment efficacy using surface-enhanced Raman spectroscopy analysis of urine in rats with kidney transplantation or kidney disease.

BACKGROUND: Individuals who have kidney disease or kidney transplants need routine assessment of their kidney damage and function, which are largely measured based on histological examination of kidney biopsies, blood test, and urinalysis. These methods are practically difficult or inconvenient, and expensive. The objective of this study was to develop a model to estimate the kidney damage and function by surface-enhanced Raman spectroscopy (SERS). METHODS: Urine samples were collected from two previous studies: renal allograft recipient Lewis rats receiving anti-TGF-ß antibody or control antibody treatment and obese diabetic ZSF1 rats with kidney disease fed with whole grape powder-containing chow or control chow. Silver nanoparticle-based SERS spectra of urine were measured. SERS spectra were analyzed using principal component analysis (PCA) combined with linear discriminant analysis (LDA) and partial least squires (PLS) analysis. RESULTS: PCA/LDA separated anti-TGF-ß antibody-treated group from control group with 90% sensitivity and 70% specificity in kidney transplants, and grape-fed group from controls with 72.7% sensitivity and 60% specificity in diabetic kidneys. The receiver operating characteristic curves showed that the integration area under the curve was 0.850 ± 0.095 (p = 0.008) in kidney transplant groups and 0.800 ± 0.097 (p = 0.02) in diabetic kidney groups. PLS predicted the biochemical parameters of kidney function using the SERS spectra, resulting in R2 = 0.8246 (p < 0.001,urine protein), R2 = 0.8438 (p < 0.001, urine creatinine), R2 = 0.9265 (p < 0.001, urea), R2 = 0.8719 (p < 0.001, serum creatinine), and R2 = 0.6014 (p < 0.001, urine protein to creatinine ratio). CONCLUSION: Urine SERS spectral analysis suggesting that it may become a convenient method for rapid assessment of renal impairment.

Torque Teno Virus for Risk Stratification of Acute Biopsy-Proven Alloreactivity in Kidney Transplant Recipients.

BACKGROUND: Drug-induced immunosuppression in kidney transplant recipients is crucial to prevent allograft rejection, but increases risk for infectious disease. Immunologic monitoring to tailor immunosuppressive drugs might prevent alloreactivity and adverse effects simultaneously. The apathogenic torque teno virus (TTV) reflects the immunocompetence of its host and might act as a potential candidate for a holistic monitoring. METHODS: We screened all 1010 consecutive patients from the prospective Vienna Kidney Transplant Cohort Study for availability of allograft biopsies and adequately stored sera for TTV quantification by polymerase chain reaction. RESULTS: Patients with acute biopsy-proven alloreactivity according to the Banff classification (n = 33) showed lower levels of TTV in the peripheral blood compared to patients without rejection (n = 80) at a median of 43 days before the biopsy. The risk for alloreactivity decreased by 10% per log level of TTV copies/mL (risk ratio, .90 [95% confidence interval, .84-.97]; P = .005). TTV levels >1 × 106 copies/mL exclude rejection with a sensitivity of 94%. Multivariable generalized linear modeling suggests an independent association between TTV level and alloreactivity. CONCLUSIONS: TTV is a prospective biomarker for risk stratification of acute biopsy-proven alloreactivity in kidney transplant recipients and might be a potential tool to tailor immunosuppressive drug therapy.

Optimizing the clinical utility of sirolimus-based immunosuppression for kidney transplantation.

While calcineurin inhibitors (CNIs) are effective for preventing acute rejection in kidney transplant recipients, long-term use may cause chronic kidney injury and is associated with increased risks of cardiovascular events, cancer, and infection-associated death. Immunosuppression strategies are needed to balance risks of acute and subclinical rejection with long-term benefits of improved kidney function. Sirolimus, an inhibitor of mammalian target of rapamycin, is used for immunosuppression in kidney transplantation. Its clinical utility has evolved, over more than 15 years, including de novo sirolimus with and without concomitant CNIs and conversion from CNI-based regimens to sirolimus. Sirolimus-containing regimens are associated with preservation of good renal function, with promising characteristics for improving long-term graft and patient survival, including antiviral and anticancer effects. Based on clinical evidence, use of low-dose sirolimus in a de novo approach with tacrolimus/steroids in the immediate posttransplantation period is appropriate. A feasible alternative is a long term, CNI-free combination with mycophenolate mofetil (following CNI-to-sirolimus conversion at 3-6 months). These strategies are appropriate for a broad range of patients with various levels of immunologic risk, including those receiving expanded criteria donor kidneys or at increased risk of delayed graft function, particular challenges in Latin America and other global regions.

Effects of marine n-3 fatty acid supplementation in renal transplantation: A randomized controlled trial.

Marine n-3 fatty acids (FAs) may exert beneficial effects on inflammation, fibrosis, and endothelial function, which could preserve renal graft function. In this randomized controlled trial, 132 Norwegian renal transplant recipients received either 2.6 g of marine n-3 FAs or olive oil (control) daily for 44 weeks, in addition to standard care. Thirty patients did not complete the trial. The primary endpoint was change (Δ) in measured glomerular filtration rate (mGFR) during follow-up. We found no significant difference in Δ mGFR between the marine n-3 FA group and controls (6.7 vs 3.8 mL/min per 1.73 m2 , P = .15). Significant beneficial effects from marine n-3 FA supplementation were, however, seen in secondary endpoints plasma triglycerides, plasma high-sensitivity C-reactive protein, and brachial artery flow-mediated dilation. In the per-protocol population, the renal graft indices percent interstitial fibrosis and Chronic Allograft Damage Index also were significantly lower in the marine n-3 FA group. The cumulative incidence of adverse events did not differ between the marine n-3 FA group (n = 218) and controls (n = 240). In conclusion, marine FA supplementation did not improve renal function compared with controls, but was safe, lowered plasma triglyceride and high-sensitivity C-reactive protein levels, and improved endothelial function (Clinical.Trials.gov identifier NCT01744067).

Screening RhoA/ROCK inhibitors for the ability to prevent chronic rejection of mouse cardiac allografts.

BACKGROUND: Chronic rejection of transplanted organs is a major obstacle in organ transplantation. The main symptoms of chronic rejection are vessel occlusion and tissue fibrosis. Macrophages play a crucial role in chronic rejection. We showed previously that RhoA deletion or RhoA/Rock inhibition using Y27632 inhibitor reorganizes macrophage actin cytoskeleton, prevents macrophage movement to the cardiac allografts, and abrogates chronic rejection in rodent models. Although besides Y27632 there are other RhoA/ROCK inhibitors available commercially, their efficacy in inhibition of chronic rejection remains unknown. METHODS: We screened four RhoA/Rock inhibitors for their ability to inhibit chronic rejection of BALB/c [H-2d] mouse cardiac allografts heterotopically transplanted into C57BL/6 [H-2b] recipients. We also tested the effect of inhibitors on macrophages in vitro. RESULTS: We found that out of four tested compounds, the Fasudil and Azaindole, inhibited vessel occlusion, tissue fibrosis, decreased M2 macrophage infiltration and abrogated chronic rejection of mouse cardiac allografts. The remaining inhibitors, SAR-407899 and SLX-2119, decreased only tissue fibrosis, and were ineffective or only slightly effective in inhibiting vessel occlusion. We also found that Azaindole and Fasudil affected actin cytoskeleton and protein expression in mouse peritoneal macrophages CONCLUSION: Results of these studies might help in development of anti-chronic rejection therapy for clinical use.

Belatacept/CTLA4Ig: an update and critical appraisal of preclinical and clinical results.

INTRODUCTION: The B7/CD28/CTLA4 signaling cascade is the most thoroughly studied costimulatory pathway and blockade with CTLA4Ig (abatacept) or its derivative belatacept has emerged as a valuable option for pharmacologic immune modulation. Several clinical studies have ultimately led to the approval of belatacept for immunosuppression in kidney transplant recipients. Areas covered: This review will discuss the immunological background of costimulation blockade and recent preclinical data and clinical results of CTLA4Ig/belatacept. Expert commentary: The development of belatacept is a major advance in clinical transplantation. However, in spite of promising results in preclinical and clinical trials, clinical use remains limited at present, in part due to increased rates of acute rejection. Recent efforts showing encouraging progress in refining such protocols might be a step toward harnessing the full potential of costimulation blockade-based immunosuppression.

Rescue case of low birth weight infant with acute hepatic failure.

We report a case involving a rescued low birth weight infant (LBWI) with acute liver failure. CASE: The patient was 1594 g and 323/7 gestational wk at birth. At the age of 11 d, she developed acute liver failure due to gestational alloimmune liver disease. Exchange transfusion and high-dose gamma globulin therapy were initiated, and body weight increased with enteral nutrition. Exchange transfusion was performed a total of 33 times prior to living donor liver transplantation (LDLT). Her liver dysfunction could not be treated by medications alone. At 55 d old and a body weight of 2946 g, she underwent LDLT using an S2 monosegment graft from her mother. Three years have passed with no reports of intellectual disability or liver dysfunction. LBWIs with acute liver failure may be rescued by LDLT after body weight has increased to over 2500 g.

Immunosuppressive agents in adult kidney transplantation in the National Health Service: a model-based economic evaluation.

BACKGROUND: Immunosuppression is required in kidney transplantation to prevent rejection and prolong graft survival. We conducted an economic evaluation to support England's National Institute for Health and Care Excellence in developing updated guidance on the use of immunosuppression, incorporating new immunosuppressive agents, and addressing changes in pricing and the evidence base. METHODS: A discrete-time state transition model was developed to simulate adult kidney transplant patients over their lifetime. A total of 16 different regimens were modelled to assess the cost-effectiveness of basiliximab and rabbit anti-thymocyte globulin (rabbit ATG) as induction agents (with no antibody induction as a comparator) and immediate-release tacrolimus, prolonged-release tacrolimus, mycophenolate mofetil, mycophenolate sodium, sirolimus, everolimus and belatacept as maintenance agents (with ciclosporin and azathioprine as comparators). Graft survival was extrapolated from acute rejection rates, graft function and post-transplant diabetes rates, all estimated at 12 months post-transplantation. National Health Service (NHS) and personal social services costs were included. Cost-effectiveness thresholds of £20 000 and £30 000 per quality-adjusted life year were used. RESULTS: Basiliximab was predicted to be more effective and less costly than rabbit ATG and induction without antibodies. Immediate-release tacrolimus and mycophenolate mofetil were cost-effective as maintenance therapies. Other therapies were either more expensive and less effective or would only be cost-effective if a threshold in excess of £100 000 per quality-adjusted life year were used. CONCLUSIONS: A regimen comprising induction with basiliximab, followed by maintenance therapy with immediate-release tacrolimus and mycophenolate mofetil, is likely to be effective for uncomplicated adult kidney transplant patients and a cost-effective use of NHS resources.

Efficacy of Cordyceps sinensis as an adjunctive treatment in kidney transplant patients: A systematic-review and meta-analysis.

OBJECTIVES: Cordyceps sinensis (cordyceps) is a fungus used in traditional Chinese medicine as adjuvant immunosuppressive agent in patients with kidney transplant. This review evaluates current evidence on the efficacy and safety of natural and fermented cordyceps preparations in patients with kidney transplant. METHODS: English and Chinese electronic databases including The Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, and CNKI (China National Knowledge Infrastructure) were searched up to December 2015 for relevant randomized controlled trials. Journals and conference proceedings were also searched. Two review authors independently selected trials for inclusion, extracted data, and assessed methodological quality. The primary outcome measures were incidence of acute graft rejection in the first year post-transplantation, one-year graft survival rate (defined as the percentage of patients with functioning grafts) and patient survival rate (or all-cause mortality). RESULTS: Nine studies were eligible for inclusion. These studies were considered to be at moderate risk of bias due to poor reporting of methods. Four studies that compared cordyceps-based therapy with azathioprine-based therapy gave comparable acute rejection rates, and graft and patient survival. The cordyceps-treated group however showed better kidney function and lower incidences of hyperuricemia, hyperlipidemia, hyperglycemia and liver injury. Cordyceps used with different combinations of immunosuppressant therapy showed significant reduction in proteinuria after 6-12 months. Compared to the group receiving cyclosporine A monotherapy, treatment with a combination of cordyceps and cyclosporine A showed less treatment-induced nephrotoxicity. Adverse events were either not monitored or poorly documented in most trials. CONCLUSIONS: Current evidence shows that cordyceps as an adjuvant to routine immunosuppressant therapy may benefit kidney transplant patient, however, better quality evidence is still required.

Protective Effects of L-Carnitine Against Delayed Graft Function in Kidney Transplant Recipients: A Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

OBJECTIVE: Delayed graft function (DGF) is an early complication after deceased donor kidney transplantation with significant adverse effects on graft outcomes. Ischemia-reperfusion injury during transplantation is a major cause of DGF. Tissue concentrations of carnitine, an antioxidant and regulator of cellular energy supply, decrease in the kidney following ischemia-reperfusion insult. Based on promising animal data, this study evaluated the possible protective effect of L-carnitine against DGF. DESIGN: This study is a pilot, randomized, double-blind, placebo-controlled clinical trial that was conducted on kidney transplantation patients in kidney transplant ward of Imam Khomeini hospital complex affiliated to Tehran University of Medical Sciences, Tehran, Iran. SUBJECTS: Patients older than 14 years old undergoing their first kidney transplantation from a deceased donor were evaluated for eligibility to take part in this study. Fifty-six patients were randomly assigned to L-carnitine or placebo groups. INTERVENTION: During this trial, 3 g of oral L-carnitine or placebo was administered in 3 divided doses each day for 4 consecutive days starting the day before kidney transplantation (i.e., days -1, 0, 1, and 2). MAIN OUTCOME MEASURE: The need for dialysis within the first week after transplantation, serum creatinine and urine output were assessed daily. After hospital discharge, patients were followed for 3 months regarding organ function. RESULTS: DGF incidence did not differ between the L-carnitine and placebo groups (18.51% vs. 23.8%, respectively; P = .68). Total allograft failure within 3 months after kidney transplantation happened in 6 patients in the placebo and 1 patient in the L-carnitine group (P = .05). CONCLUSION: This study showed no protective effects of oral L-carnitine supplementation against DGF occurrence recipients; however, 3-month graft loss was lower in the L-carnitine supplemented group.

Toward Clinical use of the IgG Specific Enzymes IdeS and EndoS against Antibody-Mediated Diseases.

The endoglycosidase EndoS and the protease IdeS from the human pathogen Streptococcus pyogenes are immunomodulating enzymes hydrolyzing human IgG. IdeS cleaves IgG in the lower hinge region, while EndoS hydrolyzes the conserved N-linked glycan in the Fc region. Both enzymes are remarkably specific for human IgG that after hydrolysis loses most of its effector functions, such as binding to leukocytes and complement activation, all contributing to bacterial evasion of adaptive immunity. However, taken out of their infectious context, we and others have shown that IdeS and EndoS can alleviate autoimmune disease in a number of animal models of antibody-mediated disorders. In this chapter, we will briefly describe the discovery and characterization of these unique enzymes, present the findings from a number of animal models of autoimmunity where the enzymes have been tested, and outline the ongoing clinical testing of IdeS. Furthermore, we will discuss the rationale for further development of IdeS and EndoS into novel pharmaceuticals against diseases where IgG antibodies contribute to the pathology, including, but not restricted to, chronic and acute autoimmunity, transplant rejection, and antidrug antibody reactions.

Medicinal herbs Fructus corni and Semen cuscutae suppress allograft rejection via distinct immune mechanisms.

Achieving long-term allograft survival without continuous global immunosuppression is highly desirable because constant immunosuppression causes severe side effects. Traditional Chinese medicine (TCM) has been utilized to treat numerous diseases for centuries. To seek novel immunosuppressive agents, we investigated several Chinese herbal formulas that have been shown to be effective in treating autoimmune diseases. C57BL/6 mice were transplanted with a skin graft from Balb/C donors and treated orally with the TCM. IL-12-expressing dendritic cells and CD4+FoxP3+ Tregs were quantified by flow cytometer while intragraft IL-12 gene expression was measured by real-time PCR. Here we identified a unique TCM, San Si formula, which contains three herbs: Fructus corni (FC), Fructus ligustri lucidi (FLL) and Semen cuscutae (SC). We found that either SC or FC, but not FLL, significantly prolonged skin allograft survival while SC plus FC or San Si formula further delayed allograft rejection compared to SC or FC alone. SC and FC, which did not contain cyclosporine and rapamycin, reduced graft-infiltrating T cells and suppressed their proliferation. Importantly, it was SC, but not FC, that induced CD4+FoxP3+ Tregs in recipients. Tregs induced by SC were also more potent in suppression. In contrast, FC repressed both intracellular IL-12 expression by intragraft DCs and IFNγ expression by graft-infiltrating T cells. Moreover, FC inhibited intragraft IL-12 gene expression. Depleting Tregs and providing exogenous IL-12 completely reversed allograft survival induced by SC plus FC. Thus, SC and FC synergistically suppress allograft rejection via distinct mechanisms.

Oridonin suppresses transplant rejection by depleting T cells from the periphery.

Oridonin is a natural compound purified from Rabdosia rubescens that has remarkable anti-inflammatory and antitumor activities. Although oridonin has been used in traditional Chinese medicine for many years to treat inflammatory diseases, the underlying mechanisms of these activities are not well understood. In this paper, we explored whether oridonin could be used in transplantation and the mechanisms of its immunosuppression. Oridonin efficacy in transplantation is manifested by prolonged graft survival and decreased graft infiltration. Oridonin induces T cell apoptosis in a concentration- and time-dependent manner. In vivo, oridonin depleted large numbers of T cells from the spleen and peripheral blood. Decreased T cell numbers resulted from apoptosis, which was accompanied by increased phagocyte numbers in the periphery. Reduction in the number of thymocytes was observed in mice treated for 8days, and CD4+CD8+ cells were more sensitive to apoptosis induced by oridonin. Additionally, successive treatment with oridonin for 16days resulted in a considerable reduction in the total number of spleen cells and spleen volume. Thus, T cell depletion may play an essential role in prolonged graft survival and immunosuppression induced by oridonin.

Immunosuppressive effects of Euphorbia hirta in experimental animals.

Euphorbia hirta L. (Euphorbiaceae) (E. hirta) is a tree locally used as a traditional medicine in Africa and Australia to treat numerous diseases such as hypertension, respiratory ailments, tumors, wounds, antipyretic, anti-inflammatory activities, etc. Therefore, we undertook to investigate their immunomodulatory effect on T lymphocytes (CD3+, CD4+ and CD8+ receptors) and Th1 cytokines (IL-2, TNF-α, IFN-γ) in a dose-dependent manner. E. hirta ethanol extract at 25, 50, 100 and 200 mg/kg doses was given orally for 7 days from the day of immunization. E. hirta maximum inhibition at 100 and 200 mg/kg p.o. was found to significantly block the production of the cell-mediated immune response, (CD3+, CD4+ and CD8+ receptors) and (IL-2, TNF-α, IFN-γ) and also prolongs graft rejection. E. hirta also showed a decrease of delayed hypersensitivity (DTH) response and dose-related decrease in the primary antibody response, respectively. Based on the data, it can be suggested that E. hirta is a potent and non-toxic immunosuppressor, which can be further explored for the development of potent immunosuppressor.

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

BACKGROUND AND OBJECTIVE: Natural killer T (NKT)-like cells are a small but significant population of T lymphocytes; however, their role in lung transplant and the effect of current immunosuppressive agents on their function is largely unknown. We have previously shown lung transplant rejection was associated with an increase in peripheral blood T cell γ-interferon (IFN-γ), tumour necrosis factor-α (TNF-α) and granzyme B. NKT-like cells are a source of these pro-inflammatory mediators and as such may be involved in lung transplant pathology. METHODS: We analysed NKT-like cell numbers and cytokine and granzyme profiles in peripheral blood from a group of stable lung transplant patients and control subjects using multiparameter flow cytometry. RESULTS: There was a significant increase in NKT-like cells in transplant patients compared with control subjects (6.8 ± 4.9 vs 0.8 ± 0.2% lymphocytes respectively). There was an increase in the numbers of NKT-like cells producing IFN-γ, TNF-α, IL-2 IL-17, granzyme and perforin in transplant patients compared with controls. Immunosuppressant drugs were less effective at inhibiting IFN-γ and TNF-α production by T and NKT-like cells than NK cells in vitro. CONCLUSIONS: 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.