Tetsuya Tajima

All Publications

• Interleukin-33 and liver natural killer cells: A novel perspective on antitumor activity in liver fibrosis. Hepatology research : the official journal of the Japan Society of Hepatology Imaoka, Y., Ohira, M., Imaoka, K., Bekki, T., Nakano, R., Yano, T., Tanaka, Y., Nakayama, T., Akabane, M., Tajima, T., Yokota, S., Krams, S. M., Martinez, O. M., Esquivel, C. O., Sasaki, K., Ohdan, H. 2024

  Abstract

  Liver fibrosis, heralding the potential progression to cirrhosis and hepatocellular carcinoma (HCC), compromises patient survival and augments post-hepatectomy recurrence. This study examined the detrimental effects of liver fibrosis on the antitumor functions of liver natural killer (NK) cells and the interleukin-33 (IL-33) signaling pathway.Our investigation, anchored in both human physiologies using living and deceased donor livers and the carbon tetrachloride (CCl4)-induced mouse fibrosis model, aimed to show a troubling interface between liver fibrosis and weakened hepatic immunity.The Fibrosis-4 (FIB-4) index emerged as a salient, non-invasive prognostic marker, and its elevation correlated with reduced survival and heightened recurrence after HCC surgery even after propensity matching (n = 385). We established a strong correlation between liver fibrosis and liver NK cell dysfunction by developing a method for extracting liver NK cells from the liver graft perfusate. Furthermore, liver fibrosis ostensibly disrupted chemokines and promoted IL-33 expression, impeding liver NK cell antitumor activities, as evidenced in mouse models. Intriguingly, our results implicated IL-33 in diminishing the antitumor responses of NK cells. This interrelation, consistent across both mouse and human studies, coincides with clinical data suggesting that liver fibrosis predisposes patients to an increased risk of HCC recurrence.Our study revealed a critical relationship between liver fibrosis and compromised tumor immunity, emphasizing the potential interference of IL-33 with NK cell function. These insights advocate for advanced immunostimulatory therapies targeting cytokines, such as IL-33, aiming to bolster the hepatic immune response against HCC in the context of liver fibrosis.

  View details for DOI 10.1111/hepr.14102

  View details for PubMedID 39134448

• Chronological alterations in de novo malignancies after living-donor liver transplantation: A cohort study of 1781 recipients using annual comparisons of standardized incidence ratios JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES Tajima, T., Hata, K., Tanaka, K., Iyama, N., Kusakabe, J., Kageyama, S., Ogawa, E., Okamoto, T., Haga, H., Uemoto, S., Hatano, E. 2024

  Abstract

  De novo malignancies (DNMs) are a major adverse event after solid organ transplantation; however, their characteristics and recent trends after living-donor liver transplantation (LDLT) remain unclear.We retrospectively reviewed 1781 primary LDLT recipients (1990-2020) and annually calculated standardized incidence ratios (SIRs) of DNMs compared to the age-adjusted Japanese general population.After 21 845 person-years follow-up, 153 DNM lesions (8.6%) were identified in 131 patients (7.4%). The incidence was 0.007 person-years. DNMs included 81 post-transplant lymphoproliferative disorders (PTLDs), 14 colorectal, 12 lung, and 12 gastric cancers, and so on. Comorbid DNMs significantly worsened recipient survival than those without (p < .001). The 5- and 10-year recipient survival after DNM diagnosis were 65% and 58%, respectively. Notably, SIR1993-1995: 8.12 (95% CI: 3.71-15.4, p < .001) and SIR1996-1998: 3.11 (1.34-6.12, p = .01) were significantly high, but had decreased time-dependently to SIR2005-2007: 1.31 (0.68-2.29, p = .42) and SIR2008-2010: 1.34 (0.75-2.20, p = .33), indicating no longer significant difference in DNMs development. Currently, however, SIR2014-2016: 2.27 (1.54-3.22, p < .001) and SIR2017-2019: 2.07 (1.40-2.96, p < .001) have become significantly higher again, reflecting recent aging of recipients (>50 years) and resultant increases in non-PTLD DNMs. Furthermore, characteristically in LDLT, the fewer the donor-recipient HLA-mismatches, the less the post-transplant DNMs development.DNM development after LDLT was significantly higher than in the general population due to higher PTLD incidence (1993-1998), but once became equivalent (2005-2013), then significantly increased again (2014-2019) due to recent recipient aging and resultant increase in solid cancers.

  View details for DOI 10.1002/jhbp.12002

  View details for Web of Science ID 001240541800001

  View details for PubMedID 38845404

• Epstein-Barr virus-associated post-transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States. Pediatric transplantation Tajima, T., Martinez, O. M., Bernstein, D., Boyd, S. D., Gratzinger, D., Lum, G., Sasaki, K., Tan, B., Twist, C. J., Weinberg, K., Armstrong, B., Desai, D. M., Mazariegos, G. V., Chin, C., Fishbein, T. M., Tekin, A., Venick, R. S., Krams, S. M., Esquivel, C. O. 2024; 28 (4): e14763

  Abstract

  Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) is the most common malignancy in children after transplant; however, difficulties for early detection may worsen the prognosis.The prospective, multicenter, study enrolled 944 children (≤21 years of age). Of these, 872 received liver, heart, kidney, intestinal, or multivisceral transplants in seven US centers between 2014 and 2019 (NCT02182986). In total, 34 pediatric EBV+ PTLD (3.9%) were identified by biopsy. Variables included sex, age, race, ethnicity, transplanted organ, EBV viral load, pre-transplant EBV serology, immunosuppression, response to chemotherapy and rituximab, and histopathological diagnosis.The uni-/multivariable competing risk analyses revealed the combination of EBV-seropositive donor and EBV-naïve recipient (D+R-) was a significant risk factor for PTLD development (sub-hazard ratio: 2.79 [1.34-5.78], p = .006) and EBV DNAemia (2.65 [1.72-4.09], p < .001). Patients with D+R- were significantly more associated with monomorphic/polymorphic PTLD than those with the other combinations (p = .02). Patients with monomorphic/polymorphic PTLD (n = 21) had significantly more EBV DNAemia than non-PTLD patients (p < .001) and an earlier clinical presentation of PTLD than patients with hyperplasias (p < .001), within 6-month post-transplant. Among non-liver transplant recipients, monomorphic/polymorphic PTLD were significantly more frequent than hyperplasias in patients ≥5 years of age at transplant (p = .01).D+R- is a risk factor for PTLD and EBV DNAemia and associated with the incidence of monomorphic/polymorphic PTLD. Intensive follow-up of EBV viral load within 6-month post-transplant, especially for patients with D+R- and/or non-liver transplant recipients ≥5 years of age at transplant, may help detect monomorphic/polymorphic PTLD early in pediatric transplant.

  View details for DOI 10.1111/petr.14763

  View details for PubMedID 38682750

• Application of Mass Cytometry Platforms to Solid Organ Transplantation. Transplantation Zhang, W., Sen, A., Pena, J. K., Reitsma, A., Alexander, O. C., Tajima, T., Martinez, O. M., Krams, S. M. 2024

  Abstract

  Transplantation serves as the cornerstone of treatment for patients with end-stage organ disease. The prevalence of complications, such as allograft rejection, infection, and malignancies, underscores the need to dissect the complex interactions of the immune system at the single-cell level. In this review, we discuss studies using mass cytometry or cytometry by time-of-flight, a cutting-edge technology enabling the characterization of immune populations and cell-to-cell interactions in granular detail. We review the application of mass cytometry in human and experimental animal studies in the context of transplantation, uncovering invaluable contributions of the tool to understanding rejection and other transplant-related complications. We discuss recent innovations that have the potential to streamline and standardize mass cytometry workflows for application to multisite clinical trials. Additionally, we introduce imaging mass cytometry, a technique that couples the power of mass cytometry with spatial context, thereby mapping cellular interactions within tissue microenvironments. The synergistic integration of mass cytometry and imaging mass cytometry data with other omics data sets and high-dimensional data platforms to further define immune dynamics is discussed. In conclusion, mass cytometry technologies, when integrated with other tools and data, shed light on the intricate landscape of the immune response in transplantation. This approach holds significant potential for enhancing patient outcomes by advancing our understanding and facilitating the development of new diagnostics and therapeutics.

  View details for DOI 10.1097/TP.0000000000004925

  View details for PubMedID 38467594

• The impact of colonic allograft inclusion on intestinal transplantation outcomes: Results from UNOS/OPTN database analysis. Clinical transplantation Matsushima, H., Sasaki, K., Nair, A., Tajima, T., Soyama, A., Eguchi, S., Hashimoto, K., Fujiki, M. 2023: e15213

  Abstract

  Outcomes of intestinal transplantation with colon allograft (ICTx) remain controversial. We aimed to assess the outcomes of ICTx in comparison to intestinal transplantation without colon (ITx) using the UNOS/OPTN registry database.We retrospectively reviewed 2612 patients who received primary intestinal transplants from 1998 to 2020. The rates of acute rejection (AR) within 6 months after transplant were compared between ICTx and ITx. Risk factors of 6-month AR were examined using logistic regression model by era. Furthermore, conditional graft survival was analyzed to determine long-term outcomes of ICTx.Of 2612 recipients, 506 (19.4%) received ICTx. Graft and patient survival in ICTx recipients were comparable to those in ITx recipients. White ICTx recipients had a higher incidence of AR within 6 months compared to ITx during the entire study period (p = .002), colonic inclusion did not increase the risk of 6-month AR in the past decade. ICTx recipients who experienced 6-month AR had worse graft and patient survival compared to those who did not (p <.001 and p = .004, respectively). Among patients who did not develop 6-month AR, Cox proportional hazard model analysis revealed that colonic inclusion was independently associated with improved conditional graft survival.In the recent transplant era, colonic inclusion is no longer associated with a heightened risk of 6-month AR and may provide better long-term survival compared to ITx when AR is absent. Risk adjustment for rejection and proper immunosuppressive therapy are crucial to maximize the benefits of colonic inclusion.

  View details for DOI 10.1111/ctr.15213

  View details for PubMedID 38064299

• Reappraisal of Donor Age in Liver Transplantation: NASH as a Potential Target to Safely Utilize Old Liver Grafts. Transplantation Kusakabe, J., Kozato, A., Tajima, T., Bekki, Y., Fujiki, M., Tomiyama, K., Nakamura, T., Matsushima, H., Hashimoto, K., Sasaki, K. 2023

  Abstract

  BACKGROUND: With the chronic shortage of donated organs, expanding the indications for liver transplantation (LT) from older donors is critical. Nonalcoholic steatohepatitis (NASH) stands out because of its unique systemic pathogenesis and high recurrence rate, both of which might make donor selection less decisive. The present study aims to investigate the usefulness of old donors in LT for NASH patients.METHODS: The retrospective cohort study was conducted using the Scientific Registry Transplant Recipient database. The cohort was divided into 3 categories according to donor age: young (aged 16-35), middle-aged (36-59), and old donors (60-). Multivariable and Kaplan-Meier analyses were performed to compare the risk of donor age on graft survival (GS).RESULTS: A total of 67 973 primary adult donation-after-brain-death LTs (2002-2016) were eligible for analysis. The multivariable analysis showed a reduced impact of donor age on GS for the NASH cohort (adjusted hazard ratio = 1.13, 95% confidence interval, 1.00-1.27), comparing old to middle-aged donors. If the cohort was limited to NASH recipients plus 1 of the following, recipient age ≥60, body mass index <30, or Model of End Stage Liver Disease score <30, adjusted hazard ratios were even smaller (0.99 [0.84-1.15], 0.92 [0.75-1.13], or 1.04 [0.91-1.19], respectively). Kaplan-Meier analysis revealed no significant differences in overall GS between old- and middle-aged donors in these subgroups (P = 0.86, 0.28, and 0.11, respectively).CONCLUSIONS: Donor age was less influential for overall GS in NASH cohort. Remarkably, old donors were equivalent to middle-aged donors in subgroups of recipient age ≥60, recipient body mass index <30, or Model of End Stage Liver Disease score <30.

  View details for DOI 10.1097/TP.0000000000004865

  View details for PubMedID 37990355

• Cost-Effectiveness Analysis of Adult Living-Donor Liver Transplantation in Japan. Hepatology research : the official journal of the Japan Society of Hepatology Tajima, T., Shin, J., Kunisawa, S., Sasaki, N., Hata, K., Fushimi, K., Hatano, E., Imanaka, Y. 2023

  Abstract

  AIM: Living-donor liver transplantation (LDLT) is a highly effective life-saving procedure; however, it requires substantial medical resources, and the cost-effectiveness of LDLT vs. conservative management (CM) for adult patients with end-stage liver disease (ESLD) remains unclear in Japan.METHODS: We conducted a cost-effectiveness analysis using the Diagnostic Procedure Combination (DPC) data from the nationwide database of the DPC research group. We selected adult patients (18 years or older) who were admitted or discharged between 2010 and 2021 with a diagnosis of ESLD with Child-Pugh classes C or B. A decision tree and Markov model were constructed, and all event probabilities were computed in 3-month cycles over a 10-year period. The willingness-to-pay per quality-adjusted life-year (QALY) was set at 5 million JPY (49,801 USD) from the perspective of the public healthcare payer.RESULTS: After propensity score matching, we identified 1,297 and 111,849 patients in the LDLT and CM groups, respectively. The incremental cost-effectiveness ratio (ICER) for LDLT vs. CM for Child-Pugh classes C and B was 2.08 million JPY/QALY (20,708 USD/QALY) and 5.24 million JPY/QALY (52,153 USD/QALY), respectively. The cost-effectiveness acceptability curves showed the probabilities of being below the willingness-to-pay of 49,801 USD/QALY as 95.4% in class C and 48.5% in class B. Tornado diagrams revealed all variables in class C were below 49,801USD/QALY while their ranges included or exceeded 49,801USD/QALY in class B.CONCLUSIONS: LDLT for adult patients with Child-Pugh class C was cost-effective compared with CM, whereas LDLT versus CM for class B patients was not cost-effective in Japan. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/hepr.13992

  View details for PubMedID 37985222

• Impact of Induction Therapy on Rejection in Pediatric Transplantation: A Multicenter Study in the US Tajima, T., Chin, C., Desai, D. M., Fishbein, T. M., Mazariegos, G. V., Tekin, A., Venick, R., Krams, S. M., Martinez, O. M., Esquivel, C. O. LIPPINCOTT WILLIAMS & WILKINS. 2023: S495

  View details for Web of Science ID 001094086301480

• 311.2: Risk factors for Epstein-Barr virus DNAemia in pediatric transplantation: A multicenter study in the United States. Transplantation Tajima, T., Bernstein, D., Boyd, S. D., Gratzinger, D., Lum, G., Sasaki, K., Tan, B., Weinberg, K., Armstrong, B., Brown, M., Chin, C., Desai, D., Fishbein, T. M., Mazariegos, G., Robien, M. A., Tekin, A., Twist, C. J., Venick, R. S., Krams, S. M., Martinez, O. M., Esquivel, C. O. 2023; 107 (10S1): 71-72

  View details for DOI 10.1097/01.tp.0000993400.94644.c0

  View details for PubMedID 37845955

• Reply: We still need to deal with antibody-mediated rejection in living donor liver transplantation LIVER TRANSPLANTATION Tajima, T., Hata, K., Kusakabe, J., Hatano, E. 2023; 29 (8): E22-E23

  View details for DOI 10.1097/LVT.0000000000000134

  View details for Web of Science ID 001033608800002

  View details for PubMedID 36964639

• Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation LIVER TRANSPLANTATION Tajima, T., Hata, K., Haga, H., Kusakabe, J., Kageyama, S., Yurugi, K., Hishida, R., Zhao, X., Nishikori, M., Nagao, M., Takaori-Kondo, A., Uemoto, S., Hatano, E. 2023; 29 (7): 711-723

  Abstract

  Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18 y) after rituximab introduction (2004-2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without ( p =0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63-16.3], p =0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05-10.0], p =0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not ( p =0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009-2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development ( p <0.001); however, it did not affect the 5-year recipient survival compared with those without ( p =0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.

  View details for DOI 10.1097/LVT.0000000000000084

  View details for Web of Science ID 001016385700009

  View details for PubMedID 36749821

• Epstein-Barr virus-associated post-transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States Tajima, T., Bernstein, D., Boyd, S. D., Gratzinger, D., Lum, G., Sasaki, K., Tan, B., Twist, C. J., Weinberg, K., Robien, M. A., Brown, M., Armstrong, B., Desai, D., Mazariegos, G., Chin, C., Fishbein, T. M., Tekin, A., Venick, R. S., Martinez, O. M., Krams, S. M., Esquivel, C. O. WILEY. 2023

  View details for Web of Science ID 001002465500078

• Anti-complement 5 antibody ameliorates antibody-mediated rejection after liver transplantation in rats. Frontiers in immunology Tajima, T., Hata, K., Kusakabe, J., Miyauchi, H., Badshah, J. S., Kageyama, S., Zhao, X., Kim, S., Tsuruyama, T., Kirchner, V. A., Watanabe, T., Uemoto, S., Hatano, E. 2023; 14: 1186653

  Abstract

  Antibody-mediated rejection (AMR) remains a refractory rejection after donor-specific antibody (DSA)-positive or blood-type incompatible liver transplantation (LT), even in the era of pre-transplant rituximab desensitization. This is due to the lack of not only effective post-transplant treatments but also robust animal models to develop/validate new interventions. Orthotopic LT from male Dark Agouti (DA) to male Lewis (LEW) rats was used to develop a rat LT-AMR model. LEW were pre-sensitized by a preceding skin transplantation from DA 4-6 weeks before LT (Group-PS), while sham procedure was performed in non-sensitized controls (Group-NS). Tacrolimus was daily administered until post-transplant day (PTD)-7 or sacrifice to suppress cellular rejections. Using this model, we validated the efficacy of anti-C5 antibody (Anti-C5) for LT-AMR. Group-PS+Anti-C5 received Anti-C5 intravenously on PTD-0 and -3. Group-PS showed increased anti-donor (DA) antibody-titers (P <0.001) and more C4d deposition in transplanted livers than in Group-NS (P <0.001). Alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bile acid (TBA), and total bilirubin (T-Bil) were all significantly higher in Group-PS than in Group-NS (all P <0.01). Thrombocytopenia (P <0.01), coagulopathies (PT-INR, P =0.04), and histopathological deterioration (C4d+h-score, P <0.001) were also confirmed in Group-PS. Anti-C5 administration significantly lowered anti-DA IgG (P <0.05), resulting in decreased ALP, TBA, and T-Bil on PTD-7 than in Group-PS (all P <0.01). Histopathological improvement was also confirmed on PTD-1, -3, and -7 (all P <0.001). Of the 9,543 genes analyzed by RNA sequencing, 575 genes were upregulated in LT-AMR (Group-PS vs. Group-NS). Of these, 6 were directly associated with the complement cascades. In particular, Ptx3, Tfpi2, and C1qtnf6 were specific to the classical pathway. Volcano plot analysis identified 22 genes that were downregulated by Anti-C5 treatment (Group-PS+Anti-C5 vs. Group-PS). Of these, Anti-C5 significantly down-regulated Nfkb2, Ripk2, Birc3, and Map3k1, the key genes that were amplified in LT-AMR. Notably, just two doses of Anti-C5 only on PTD-0 and -3 significantly improved biliary injury and liver fibrosis up to PTD-100, leading to better long-term animal survival (P =0.02). We newly developed a rat model of LT-AMR that meets all the Banff diagnostic criteria and demonstrated the efficacy of Anti-C5 antibody for LT-AMR.

  View details for DOI 10.3389/fimmu.2023.1186653

  View details for PubMedID 37398677

• Impact of the donor hepatectomy time on short-term outcomes in liver transplantation using donation after circulatory death: A review of the US national registry. Clinical transplantation Bekki, Y., Kozato, A., Kusakabe, J., Tajima, T., Fujiki, M., Gallo, A., Melcher, M. L., Bonham, C. A., Sasaki, K. 2022: e14778

  Abstract

  BACKGROUND: During the donor hepatectomy time (dHT), defined as the time from the start of cold perfusion to the end of the hepatectomy, liver grafts have a suboptimal temperature. The aim of this study was to analyze the impact of prolonged dHT on outcomes in donation after circulatory death (DCD) liver transplantation (LT).METHODS: Using the US national registry data between 2012 and 2020, DCD LT patients were separated into 2 groups based on their dHT: standard dHT (<42 min) and prolonged dHT (≥42 min).RESULTS: There were 3810 DCD LTs during the study period. Median dHT was 32 min (IQR 25-41 min). Kaplan- Meier graft survival curves demonstrated inferior outcomes in the prolonged dHT group at 1-year after DCD LT compared to those in the standard dHT group (85.3% vs 89.9%; p < 0.01). Multivariate Cox proportional hazards models for 1-year graft survival identified that prolonged dHT [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.19 - 1.79], recipient age ≥ 64 years (HR 1.40, 95% CI 1.14 - 1.72), and MELD score ≥ 24 (HR 1.43, 95% CI 1.16 - 1.76) were significant predictors of 1-year graft loss. Spline analysis shows that the dHT effects on the risk for 1-year graft loss with an increase in the slope after median dHT of 32 min.CONCLUSION: Prolonged dHTs significantly reduced graft and patient survival after DCD LT. Because dHT is a modifiable factor, donor surgeons should take on cases with caution by setting the dHT target of < 32 min. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.14778

  View details for PubMedID 35866342