Research Spotlight

Elsiesy, H., M. Shawakat, W. Alhamoudi, M. Alsebayel, J. Renz, H. Elbeshbeshy, M. Abdelfattah and F. Abaalkhail (2019). “Donor-to-recipient transmission of factor XII deficiency by orthotopic liver transplantation.” Proc (Bayl Univ Med Cent) 32(4): 596-598.

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Transmission of congenital clotting factor deficiencies following orthotopic liver transplantation is rare. There has been one reported case of donor-to-recipient transmission of factor XII deficiency in a transplant, and we report the second case.

Aggarwal, A., N. Jaswal, R. Jain and H. Elsiesy (2019). “Amoxicillin-clavulanate-induced Granulomatous Hepatitis: Case Report and Review of the Literature.” J Clin Transl Hepatol 7(3): 280-283.

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Amoxicillin-clavulanate (AC) is a common cause of drug-induced liver injury, either cholestatic or mixed with hepatitis pattern. Rarely, AC causes granulomatous hepatitis. We report a new case of AC-induced granulomatous hepatitis documented by liver biopsy, with complete resolution of any histological sequelae on a follow-up liver biopsy after AC was withdrawn.

Modi, A. A., H. Nazario, J. F. Trotter, M. Gautam, J. Weinstein, P. Mantry, M. Barnes, A. Habib, J. McAfee, O. Teachenor, L. Tujague and S. Gonzalez (2016). “Safety and efficacy of simeprevir plus sofosbuvir with or without ribavirin in patients with decompensated genotype 1 hepatitis C cirrhosis.” Liver Transpl 22(3): 281-286

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Combination antiviral therapy involving sofosbuvir (SOF) and simeprevir (SIM) is a treatment option in patients with genotype 1 chronic hepatitis C; however, the safety of this regimen in patients with decompensated cirrhosis is not established. Data from a combined treatment cohort of 2 large hepatology referral centers were evaluated to assess for safety and efficacy of SIM plus SOF with or without ribavirin (RBV) in patients with Child B or C cirrhosis. All (n = 42) patients included in the analysis had Child B (n = 35) or C (n = 7) cirrhosis and received 400 mg daily of SOF plus 150 mg daily of SIM, with (n = 7) or without (n = 35) RBV, for 12 weeks. Of the 42 patients in this cohort, 31 (74%) were male, 22 (52%) had failed prior treatments, and 28 (67%) were genotype 1a. Prior decompensating events included encephalopathy (57%), fluid overload (88%), or variceal hemorrhage (24%). Median Model for End-Stage Liver Disease score was 12 (range, 6-25). Treatment was well tolerated overall with more than one-half (57%) reporting no adverse events. In those reporting adverse events, the most common were fatigue (n = 6), insomnia (n = 4), headache (n = 5), nausea (n = 4), and grade 1 rash (n = 1). One patient developed chemical pancreatitis that did not require treatment discontinuation. Three of 7 patients who received RBV developed anemia, with 2 requiring blood transfusions and 1 requiring a dose reduction. No episodes of decompensation requiring hospitalization or deaths occurred on treatment. Of 42 patients, 38 (90%) patients had negative viral load at end of treatment (EOT), and 31 of 42 patients (74%) achieved sustained virological response 12 weeks after EOT; 10 of 10 patients (100%) with HCV genotype 1b achieved sustained virological response for 12 weeks (SVR12). In conclusion, SOF plus SIM was very well tolerated in patients with advanced Child B/C decompensated cirrhosis. Overall, 74% of patients achieved SVR12; 100% of patients with genotype 1b decompensated cirrhosis achieved SVR12.

Ceglia, V., S. Zurawski, M. Montes, A. Bouteau, Z. Wang, J. Ellis, B. Z. Igyártó, Y. Lévy and G. Zurawski (2021). “Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties.” J Immunol 207(8): 2060-2076.

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CD40 is a potent activating receptor within the TNFR family expressed on APCs of the immune system, and it regulates many aspects of B and T cell immunity via interaction with CD40 ligand (CD40L; CD154) expressed on the surface of activated T cells. Soluble CD40L and agonistic mAbs directed to CD40 are being explored as adjuvants in therapeutic or vaccination settings. Some anti-CD40 Abs can synergize with soluble monomeric CD40L. We show that direct fusion of CD40L to certain agonistic anti-CD40 Abs confers superagonist properties, reducing the dose required for efficacy, notably greatly increasing total cytokine secretion by human dendritic cells. The tetravalent configuration of anti-CD40-CD40L Abs promotes CD40 cell surface clustering and internalization and is the likely mechanism of increased receptor activation. CD40L fused to either the L or H chain C termini, with or without flexible linkers, were all superagonists with greater potency than CD40L trimer. The increased anti-CD40-CD40L Ab potency was independent of higher order aggregation. Moreover, the anti-CD40-CD40L Ab showed higher potency in vivo in human CD40 transgenic mice compared with the parental anti-CD40 Ab. To broaden the concept of fusing agonistic Ab to natural ligand, we fused OX40L to an agonistic OX40 Ab, and this resulted in dramatically increased efficacy for proliferation and cytokine production of activated human CD4(+) T cells as well as releasing the Ab from dependency on cross-linking. This work shows that directly fusing antireceptor Abs to ligand is a useful strategy to dramatically increase agonist potency.

Warren, A. M., K. McMinn, G. Testa, A. E. Wall, G. Saracino, A. C. Waddimba and L. Johannesson (2021). “Psychological Characteristics of Recipients Pretransplantation in the Dallas UtErus Transplant Study (DUETS).” Prog Transplant Oct 27;15269248211046002. [Epub ahead of print]. 15269248211046002.

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INTRODUCTION: Uterus transplantation is now a viable option for fertility treatment for women with absolute uterine factor infertility. Psychological assessment is recommended as a part of the perioperative evaluation process. RESEARCH OBJECTIVE: The purpose of this study was to examine the psychological characteristics and mental health history of the 20 women who participated in the Dallas UtErus Transplant Study (DUETS) trial. DESIGN: This retrospective observational descriptive study was part of a prospective clinical trial. Prior to transplant, 20 women completed a clinical psychological interview, 19 of whom also completed psychological assessment measures including the Hospital Anxiety and Depression Scale, Patient Health Questionnaire 9 item, Generalized Anxiety Disorder 7 item, PTSD Checklist for DSM-5, 36-Item Short Form, Connor-Davidson Resilience Scale 10 item, and Dyadic Adjustment Scale. RESULTS: Women who participated in the trial had high health-related quality of life and minimal psychological history, with most reporting psychological distress associated with their initial infertility diagnosis (N = 13). None of the participants endorsed psychological distress to meet clinical concerns on the psychological measures used. Satisfaction with relationship adjustment with their partners was also high. CONCLUSIONS: Women with absolute uterine factor infertility who underwent uterus transplant demonstrated low psychological distress on assessment measures, were resilient, had high health related quality of life, and strong satisfaction with the quality of relationships with their partners. Although some women reported either current or past psychological diagnosis, most reported psychological distress that occurred at the time of the infertility diagnosis and appeared to resolve over time.