Paul M. Schroder

Can immune cell function assay identify patients at risk of infection or rejection? A meta-analysis.

Background. The Cylex ImmuKnow cell function assay (CICFA) is being considered as a possible tool for identification of infection and rejection in transplant recipients. However, the predictive capability of CICFA is still unclear. Methods. Herein, we performed a meta-analysis to assess the efficacy of CICFA in identifying risks of infection and rejection posttransplantation. After a careful review of eligible studies, sensitivity, specificity, and other measures of the accuracy of CICFA were pooled. Summary receiver operating characteristic curves were used to represent the overall test performance. Results. Nine studies met the inclusion criteria. The pooled estimates for CICFA in identification of infection risk were poor, with a sensitivity of 0.58 (95% confidence interval [CI]: 0.52–0.64), a specificity of 0.69 (95% CI: 0.66–0.70), a positive likelihood ratio of 2.37 (95% CI: 1.90–2.94), a negative likelihood ratio of 0.39 (95% CI: 0.16–0.70), and a diagnostic odds ratio of 7.41 (95% CI: 3.36–16.34). The pooled estimates for CICFA in identifying risk of rejection were also fairly poor with a sensitivity of 0.43 (95% CI: 0.34–0.52), a specificity of 0.75 (95% CI: 0.72–0.78), a positive likelihood ratio of 1.30 (95% CI: 0.74–2.28), a negative likelihood ratio of 0.96 (95% CI: 0.85–1.07), and a diagnostic odds ratio of 1.19 (95% CI: 0.65–2.20). Conclusion. The current evidence suggests that CICFA is not able to identify individuals at risk of infection or rejection. Additional studies are still needed to clarify the usefulness of this test for identifying risks of infection and rejection in transplant recipients.

Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: A meta-analysis†

Because of the severe organ shortage, living donor liver transplantation (LDLT) offers a timely alternative to deceased donor liver transplantation (DDLT) for patients with hepatocellular carcinoma (HCC). However, the higher recurrence rate of HCC after LDLT and the indication criteria remain controversial. By conducting a quantitative meta‐analysis, we sought to compare the survival outcomes and recurrence rates with LDLT and DDLT for patients with HCC. Comparative studies of LDLT and DDLT for HCC, which were identified by a comprehensive literature search, were included in this study. The evaluated outcomes included patient survival, recurrence‐free survival (RFS), and recurrence rates at defined time points. Seven studies with a total of 1310 participants were included in this study. For LDLT and DDLT recipients, we found comparable patient survival rates [1 year, odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.62‐1.73; 3 years, OR = 1.07, 95% CI = 0.77‐1.48; and 5 years, OR = 0.64, 95% CI = 0.33‐1.24] and RFS rates (1 year, OR = 0.86, 95% CI = 0.54‐1.38; 3 years, OR = 1.04, 95% CI = 0.69‐1.58; and 5 years, OR = 1.11, 95% CI = 0.70‐1.77). Moreover, we found no significant differences in the 1‐, 3‐, or 5‐year recurrence rates between LDLT and DDLT recipients (1 year, OR = 1.55, 95% CI = 0.36‐6.58; 3 years, OR = 2.57, 95% CI = 0.53‐12.41; and 5 years, OR = 1.21, 95% CI = 0.44‐3.32). A subgroup analysis revealed similar outcomes for patients with HCC meeting the Milan criteria. These findings demonstrate that for HCC patients (especially those within the Milan criteria), LDLT represents an acceptable option that does not compromise patient survival or increase HCC recurrence in comparison with DDLT. Liver Transpl 18:1226–1236, 2012.

Liver transplantation versus liver resection in the treatment of hepatocellular carcinoma: a meta-analysis of observational studies.

Background A number of cohort studies have compared the outcomes of liver transplantation (LT) and liver resection (LR) in hepatocellular carcinoma (HCC) patients. However, the effects of LT versus LR remain unclear. We searched electronic databases and reference lists for relevant articles published before February 2013. Methods The primary endpoints were pooled using random-effects models to model potential heterogeneity, including overall survival (OS), disease-free survival, and recurrence rate. Results We found similar 1-year OS (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.81–1.43; P=0.61) yet significantly better 3-year OS (OR, 1.47; 95% CI, 1.18–1.84; P<0.001) and 5-year OS (OR, 1.77; 95% CI, 1.45–2.16; P<0.001) after LT compared with LR with relative risk differences of 9% (P<0.001) and 14% (P<0.001), respectively. The 1-, 3-, and 5-year difference-free survival were 13%, 29%, and 39% higher (P<0.001 in all) in LT recipients than LR patients. Additionally, recurrence rate was 30% less (P<0.001) in LT than LR. Furthermore, better 5-year difference-free survival (P<0.001) and recurrence rates (P<0.05) were yielded after LT when patients from the entire HCC population were included. Conclusions When including all the 62 previous studies comparing LT and resection, LT provides increased survival and lower recurrence rates than LR for HCC patients. These results of disease-free survival and recurrence rate are similar among early HCC patients with Child-Turcotte-Pugh class A cirrhosis. However, summary ORs and risk differences cannot be interpreted as causal effects of LT versus LR.

Current approaches in national kidney paired donation programs

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. While living donors provide anywhere from a small to a large fraction of kidneys for transplantation in different countries, at least one-third of these donors are incompatible with their potential recipients. To overcome these challenges, kidney paired donation (KPD) programs have been established that organize donor exchanges to find matches among the pool of incompatible pairs. Each program has developed its own features to accommodate local needs. Reasons for participating in KPD include blood group incompatibility, sensitization of the recipient against the donor, and the potential for improvement in transplant quality (e.g., age difference or graft size), and tissue compatibility. KPD programs use sophisticated algorithms to find matches among the pool of donor-recipient pairs to create simultaneous 2-way, 3-way, or 4-way exchanges or more complex non-simultaneous chains of transplants. These KPD allocation systems should be medically sound and ethically acceptable according to the principles of equity, utility, and justice. The variety of possible exchanges provided by these algorithms allows for maximizing the number of transplants, increasing the quality of transplants, and accommodating patients who are difficult to match. In this review, we describe several examples of successful KPD programs with diverse organizational approaches. By highlighting the strategies used by these programs to meet the needs of their patient populations, we aim to inspire improvements in existing programs and to provide a framework for expanding KPD to better serve international transplant communities.

A Dynamic Dual Role of IL-2 Signaling in the Two-Step Differentiation Process of Adaptive Regulatory T Cells

The molecular mechanism of the extrathymic generation of adaptive, or inducible, CD4+Foxp3+ regulatory T cells (iTregs) remains incompletely defined. We show that exposure of splenic CD4+CD25+Foxp3− cells to IL-2, but not other common γ-chain cytokines, resulted in Stat5 phosphorylation and induced Foxp3 expression in ∼10% of the cells. Thus, IL-2/Stat5 signaling may be critical for Foxp3 induction in peripheral CD4+CD25+Foxp3– iTreg precursors. In this study, to further define the role of IL-2 in the formation of iTreg precursors as well as their subsequent Foxp3 expression, we designed a two-step iTreg differentiation model. During the initial “conditioning” step, CD4+CD25−Foxp3− naive T cells were activated by TCR stimulation. Inhibition of IL-2 signaling via Jak3–Stat5 was required during this step to generate CD4+CD25+Foxp3− cells containing iTreg precursors. During the subsequent Foxp3-induction step driven by cytokines, IL-2 was the most potent cytokine to induce Foxp3 expression in these iTreg precursors. This two-step method generated a large number of iTregs with relatively stable expression of Foxp3, which were able to prevent CD4+CD45RBhigh cell–mediated colitis in Rag1−/− mice. In consideration of this information, whereas initial inhibition of IL-2 signaling upon T cell priming generates iTreg precursors, subsequent activation of IL-2 signaling in these precursors induces the expression of Foxp3. These findings advance the understanding of iTreg differentiation and may facilitate the therapeutic use of iTregs in immune disorders.

Anti-TCRβ mAb induces long-term allograft survival by reducing antigen-reactive T cells and sparing regulatory T cells.

TCR specific antibodies may modulate the TCR engagement with antigen–MHC complexes, and in turn regulate in vivo T cell responses to alloantigens. Herein, we found that in vivo administration of mAbs specific for mouse TCRβ (H57–597), TCRα or CD3 promptly reduced the number of CD4+ and CD8+ T cells in normal mice, but H57–597 mAb most potently increased the frequency of CD4+Foxp3+ Treg cells. When mice were injected with staphylococcal enterotoxin B (SEB) superantigen and H57–597 mAb, the expansion of SEB‐reactive Vβ8+ T cells was completely abrogated while SEB‐nonreactive Vβ2+ T cells remained unaffected. More importantly, transient H57–597 mAb treatment exerted long‐lasting effect in preventing T cell responses to alloantigens, and produced long‐term cardiac allograft survival (>100 days) in 10 out of 11 recipients. While Treg cells were involved in maintaining donor‐specific long‐term graft survival, T cell homeostasis recovered over time and immunity was retained against third party allografts. Moreover, transient H57–597 mAb treatment significantly prolonged survival of skin allografts in naïve recipients as well as heart allografts in skin‐sensitized recipients. Thus, transient modulation of the TCRβ chain by H57–597 mAb exhibits potent, long‐lasting therapeutic effects to control alloimmune responses.

Efficacy and Tolerability of Telaprevir for Chronic Hepatitis Virus C Genotype 1 Infection: A Meta-Analysis

Background Chronic hepatitis C virus (HCV) infection is one of the leading causes of hepatic cirrhosis and hepatocellular carcinoma, and HCV genotype 1 is the most prevalent genotype and is resistant to current standard therapy. We performed this meta-analysis to evaluate the efficacy and safety of telaprevir-based therapy for chronic HCV genotype 1 infection. Methods We included randomized controlled trials with no year or language restriction. All data were analyzed using a random-effects model by Review Manager v5.0. The primary outcome was the proportion of patients achieving sustained virologic response (SVR), and the secondary outcomes were HCV relapse rate, incidence of severe adverse events (SAEs), and discontinuation due to adverse events. Results The proportion of achieving SVR was significantly higher in the telaprevir group (odds ratio [OR] = 3.40 [1.92, 6.00], P<0.0001; I2 = 87%) regardless of a patients’ previous treatment status. It was also significantly higher in the 24-week and 48-week treatment groups (OR = 4.52 [2.08, 9.81], P<0.001; I2 = 85%, and OR = 4.05 [1.56, 10.56], P = 0.004; I2 = 92%, respectively), while it was comparable in the 12-week treatment group (OR = 1.32 [0.63, 2.75], P = 0.46; I2 = 35%). In addition, the HCV relapse rate was significantly reduced in the telaprevir group (OR = 0.28 [0.16, 0.49], P<0.001; I2 = 76%). However, the incidence of SAE (OR = 1.56 [1.15, 2.10], P = 0.004; I2 = 0%) and study discontinuation due to adverse events (OR = 2.24 [1.43, 3.50], P<0.001; I2 = 37%) were significantly higher in the telaprevir group. Conclusion Despite its higher incidence of SAEs and discontinuation due to adverse events, telaprevir-based therapy can increase the proportion of achieving SVR in both previously treated and untreated chronic HCV-1 infected patients.

Early acute antibody-mediated rejection of a negative flow crossmatch 3rd kidney transplant with exclusive disparity at HLA-DP.

Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA.

Novel Sphingosine-1-Phosphate Receptor Modulator KRP203 Combined With Locally Delivered Regulatory T Cells Induces Permanent Acceptance of Pancreatic Islet Allografts

Background KRP203, a structural FTY720 analogue, has 5-fold greater selectivity for binding to sphingosine-1-phosphate receptor (S1PR) 1 (S1PR1) versus S1PR3 and 100-fold greater selectivity over S1PR2 and S1PR5. Although the immunoregulatory effects of FTY720 have been tested in clinical and experimental research, the therapeutic efficacy of KRP203 in allograft models remains elusive. In this study, we investigated the potential of KRP203 alone and in combination with intragraft injection of CD4+CD25+FoxP3+ regulatory T cells (Tregs) to induce islet allograft tolerance. Methods BALB/c (H-2d) mice received transplants of fresh C57BL/10 (H-2b) islet allografts under the kidney capsule and were treated for 7 days with 0.3, 1.0, or 3.0 mg/kg KRP203 alone or in combination with intragraft-infused Tregs. Results Untreated BALB/c mice acutely rejected C57BL/10 islet allografts at a mean survival time of 13.8±2.7 days (n=5). A 7-day dosing of 0.3 or 1.0 mg/kg KRP203 produced long-term islet allograft survival (>200 days) in one of five and two of seven recipients, respectively. A 3 mg/kg KRP203 dose resulted in islet graft survival for more than 200 days in 5 of 12 recipients. Whereas recipients that received 500 allogeneic islets admixed with 5×105–7×105 Tregs survived 83.6±67.2 days, addition of transient 3 mg/kg KRP203 therapy induced prolonged drug-free graft survival (>200 days) in all recipients. Conclusions A brief treatment with KRP203 significantly prolonged islet allograft survival, whereas additional intragraft delivery of Tregs induced tolerogenic effects selective to islet alloantigens.

Adjuvant chemotherapy for patients with primary hepatocellular carcinoma: a meta-analysis.

Numerous studies have investigated the effects of adjuvant chemotherapy for primary hepatocellular carcinoma (HCC) patients. We conducted this analysis to evaluate the efficacy of adjuvant chemotherapy in HCC patients after hepatectomy. PubMed/MEDLINE, EMBASE, Cochrane, and other databases were searched for eligible studies. The major endpoints were overall survival (OS) and disease‐free survival (DFS). The pooled odds ratio (OR) was calculated using a random‐effects model to summarize the results. In the meta‐analysis of 13 randomized control trials (RCTs) and 35 observational studies with 4747 patients, hepatectomy plus adjuvant chemotherapy showed superiority over hepatectomy alone in 1‐year DFS (OR = 1.86, 1.38–2.51, p < 0.001), 3‐year DFS (OR = 2.37, 1.73–3.24, p < 0.001) and 5‐year DFS (OR = 1.99, 1.55–2.55, p < 0.001), as well as 1‐year OS (OR = 2.16, 95% confidence interval 1.75–2.68, p < 0.001), 3‐year OS (OR = 1.77, 1.48–2.13, p < 0.001) and 5‐year OS (OR = 1.92, 1.44–2.56, p < 0.001). Subgroup and sensitivity analysis revealed that only adjuvant TACE had significant survival benefits. The meta‐analysis of studies involving patients with portal vein tumor thrombus (PVTT), but not other factors related to recurrence risk, revealed favorable outcomes of the Treatment arm over the Control arm. The present study shows that adjuvant chemotherapy can improve outcomes for HCC patients. The benefits of adjuvant TACE have been confirmed whereas the effects of other adjuvant chemotherapy modalities remain uncertain. Adjuvant chemotherapy is likely to be more applicable to certain patient populations for instance those with PVTT, but further research in identifying these patient factors is of importance for tailoring adjuvant therapies to individual patients in the future.