American Journal of Transplantation最新文献

Immunosenescence, the age-related dysregulation of innate and adaptive immunity, impairs immune response and increases inflammation, leading to higher infection and cardiovascular risks, particularly outside the field of transplantation. In kidney transplant recipients (KTRs), conditions like cytomegalovirus infection, old age, uremia, smoking, and diabetes, linked to poor outcomes, are associated with enhanced immunosenescence. Recent studies highlight the pathogenic role of cytotoxic T cells, particularly terminally differentiated effector memory T cells that reexpress CD45RA (T_EMRA), in graft dysfunction. A higher proportion of circulating CD8⁺ T_EMRA cells is observed in KTRs with chronic rejection. In antibody-mediated rejection, they invade the graft by superior chemotactic properties and binding to human leukocyte antigen (HLA) antibodies through FcγRIIIa (CD16). Also in microvascular inflammation without donor-specific antibodies, and even in patients without rejection but faster decline of kidney function, intragraft CD8⁺ T_EMRA cells were instrumental. CD8⁺ T_EMRA cells may explain the unresolved dismal graft outcomes associated with donor age and cytomegalovirus-serostatus mismatching and could become a novel therapeutic target in KTRs.

Solid organ transplant recipients (SOTRs) have a heightened risk of adverse coronavirus disease 2019 (COVID-19) outcomes because of immunosuppression and medical comorbidity. We quantified the burden of COVID-19 mortality in United States (US) SOTRs. A sample of deaths documented in the US solid organ transplant registry from June 2020 through December 2022 was linked to the National Death Index to identify COVID-19 deaths and weighted to represent all SOTR deaths during the study period. Among 505 757 SOTRs, 57 575 deaths occurred, and based on the linkage, 12 396 (21.5%) were due to COVID-19. COVID-19 mortality was higher in males (mortality rate ratio [MRR]: 1.13), SOTRs aged 65 years and older (MRR: 1.50 in ages 65-74 vs ages 55-64 years), and non-Hispanic Black and Hispanic SOTRs (MRRs: 1.55 and 1.79 vs non-Hispanic White SOTRs). Kidney and lung recipients had the highest COVID-19 mortality, followed by heart, and then liver recipients. COVID-19 mortality also varied over time and across US states. Overall, SOTRs had a 7-fold increased risk of COVID-19 death compared to the US general population. SOTRs comprised 0.13% of the US population but accounted for 1.46% of all US COVID-19 deaths. SOTRs experience greatly elevated COVID-19 mortality. Clinicians should continue to prioritize COVID-19 prevention and treatment in this high-risk population.

The distinction between autoimmune and alloimmune reactions in liver transplant recipients can be challenging. Plasma cell-rich rejection (PCRR), previously known as de novo autoimmune hepatitis or plasma cell hepatitis, is an atypical and underrecognized form of allograft rejection observed post-liver transplantation, often in conjunction with features of T cell-mediated and antibody-mediated rejection. If PCRR is not recognized and treated with prompt immunosuppressive augmentation, patients can develop advanced hepatic fibrosis, necroinflammation, and allograft failure. Given the significant morbidity and mortality associated with PCRR, there exists a need to develop noninvasive biomarkers which can be used in screening, diagnosis, and treatment monitoring of PCRR. This study is a literature review of candidate serum-based and tissue-based biomarkers in adult and pediatric liver transplant PCRR. We also discuss biomarkers from plasma cell-rich processes observed in other disease states and other organ transplant recipients that might be tested in liver transplant PCRR. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized management of PCRR.

New therapies directed against plasma cells such as anti-CD38 antibodies and the bispecific anti-B cell maturation antigen antibodies, represent not only an important advance in the treatment of multiple myeloma but have the potential to change the treatment landscape of other antibody-mediated diseases. In solid organ transplantation, the therapeutic armamentarium targeting humoral alloimmune responses in desensitization of highly sensitized transplant candidates and posttransplant antibody-mediated rejection has lagged behind advances in preventing and treating T cell-mediated rejection. Intravenous immunoglobulin and plasmapheresis are used extensively but have limited efficacy. Currently available anti-CD20 antibodies are only partially effective in achieving B cell depletion and leaving mature plasma cells untouched. Although interleukin 6 plays an important role in the humoral alloimmune response and injury, the benefits of interleukin 6 inhibition have failed to be demonstrated in clinical trials. Even proteasome inhibitors developed specifically to target plasma cells have not fulfilled their promise, due to limited efficacy as single agents. This review focuses on the recent experience with, and potential applicability of, anti-CD38 antibodies in the field of organ transplantation and experimental data supporting their use and development for human leukocyte antigen desensitization and antibody-mediated rejection.

Belatacept, a fusion protein combining cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the Fc region of human IgG1, is increasingly used as a calcineurin inhibitor-sparing regimen in patients with chronic graft dysfunction. Older kidney transplant recipients, particularly from expanded criteria donors, may be switched to belatacept due to poor renal recovery. However, late-onset cytomegalovirus (CMV) reactivation is increasingly reported with this treatment, especially in older patients with graft dysfunction. This suggests a progressive loss of CMV-specific T cell response, potentially driven by T cell exhaustion. Contributing factors include preexisting T cell dysfunction, increased viral antigen exposure, and interference in the PD-L1/PD-1 pathway by belatacept. mTOR inhibitors have shown efficacy in preventing CMV reactivation by reinvigorating CMV-specific T cells. These findings support combining belatacept with mTOR inhibitors in high-risk CMV-seropositive recipients and emphasize the need for personalized immune assessments to guide immunosuppressive strategies.

Patients receiving liver transplantation in a setting of complete portal vein (PV) and superior mesenteric vein (SMV) thrombosis (Yerdel grade 4) experience lower outcomes after surgery; prognosis is independently influenced by the portal flow reconstruction technique, showing better outcomes in physiological surgical strategies. We describe a case of living donor liver transplantation in which the patient could not receive common physiological reconstructions preoperatively due to multiple small collaterals and extensive thrombosis down to first branches of SMV. We performed thromboendovenectomy of the PV and SMV first, but acute thrombosis developed recurrently even with interposition venous homograft between pericholedochal collateral vein and proximal recipient PV. Immediate after surgery, an intervention radiologist performed stent insertion into 3 stenotic points. Through multidisciplinary approach, complete physiological recanalization was obtained with normal liver function.

Although cytomegalovirus (CMV) is a common complication after pediatric liver transplantation (PLT), the optimal method for CMV prevention is uncertain and lacks multi-centered investigation. We compared the effectiveness of short (<120d) versus long (>180d) CMV primary antiviral prophylaxis to prevent CMV disease in PLT, through a prospective cohort study of primary PLT (<18 yrs of age) recipients enrolled in the Society of Pediatric Liver Transplantation (SPLIT) registry from 2015 to 2019 with either donor or recipient CMV seropositivity. Participants were grouped into short or long prophylaxis based on their center's practice and intended duration. 199 PLT recipients were enrolled including 112 (56.3%) short and 87 (43.7%) long prophylaxis. End-organ disease was rare and similar between groups (2.7% and 1.1%; p=0.45). CMV DNAemia and syndrome were more common in the short compared to long (26.8% v. 13.8%; p=0.03 and 18.8% v. 6.9%; p=0.02). Neutropenia occurred more commonly with long prophylaxis (55.2% vs. 16.1%; p<0.001). Graft and patient survival were similar. Consideration of a short prophylaxis must weigh increased risk of CMV syndrome/DNAemia against medication burden and neutropenia of longer prophylaxis.