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The ability to induce tolerance would be a major advance in the field of solid organ transplantation. Here, we investigated whether autologous (congenic) hematopoietic stem cell transplantation (HSCT) could promote tolerance to heart allografts in mice. In an acute rejection model, fully MHC-mismatched BALB/c hearts were heterotopically transplanted into C57BL/6 (CD45.2) mice. One week later, recipient mice were lethally irradiated and reconstituted with congenic B6 CD45.1 Lin-Sca1+ckit+ cells. Recipient mice received a 14-day course of rapamycin both to prevent rejection and to expand regulatory T cells (Tregs). Heart allografts in both untreated and rapamycin-treated recipients that did not undergo HSCT were rejected within 33 days (median survival time = 8 days for untreated recipients, median survival time = 32 days for rapamycin-treated recipients), whereas allografts in HSCT-treated recipients had a median survival time of 55 days (P < 0.001 vs. both untreated and rapamycin-treated recipients). Enhanced allograft survival following HSCT was associated with increased intragraft Foxp3+ Tregs, reduced intragraft B cells, and reduced serum donor-specific antibodies. In a chronic rejection model, Bm12 hearts were transplanted into C57BL/6 (CD45.2) mice, and congenic HSCT was performed two weeks following heart transplantation. HSCT led to enhanced survival of allografts (median survival time = 70 days vs. median survival time = 28 days in untreated recipients, P < 0.01). Increased allograft survival post-HSCT was associated with prevention of autoantibody development and absence of vasculopathy. These data support the concept that autologous HSCT can promote immune tolerance in the setting of allotransplantation. Further studies to optimize HSCT protocols should be performed before this procedure is adopted clinically., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Both alloimmune and nonalloimmune factors affect the long-term survival of liver allograft recipients. Various patterns of late-onset rejection are recognized, including typical acute cellular rejection (tACR), ductopenic rejection (DuR), nonspecific hepatitis (NSH), isolated central perivenulitis (ICP), and plasma cell-rich rejection (PCRR). This study compares the clinicopathologic features of late-onset rejection (LOR) in a large-cohort context., Methods: For-cause liver biopsies more than 6 months after transplant were included from the University of Minnesota between 2014 and 2019. Histopathologic, clinical, laboratory, treatment, and other data were analyzed in nonalloimmune and LOR cases., Results: The study consisted of 160 patients (122 adults, 38 pediatric patients), with 233 (53%) biopsies showing LOR: 51 (22%) tACR; 24 (10%) DuR; 23 (10%) NSH; 19 (8%) PCRR; and 3 (1%) ICP. Mean onset of 80 vs 61 months was longer for nonalloimmune injury (P = .04), a difference lost without tACR (mean, 26 months). Graft failure was highest with DuR. Response to treatment, as measured by changes in liver function tests, was similar between tACR and other LORs, and NSH occurred more often in pediatric patients (P = .001); tACR and other LOR incidence was similar., Conclusions: LORs occur in pediatric and adult patients. Except for tACR, patterns overlap in many ways, with DuR having the greatest risk of graft loss, but other LORs respond well to antirejection treatments., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

LITMUS was a single-centre, Phase 2a study designed to investigate whether the gene biomarker FGL2/IFNG previously reported for the identification of tolerance in murine models could identify operationally tolerant liver transplant recipients. Multiplex RT-PCR was used to amplify eight immunoregulatory genes in peripheral blood mononuclear cells (PBMC) from 69 adult liver transplant recipients. Patients with PBMC FGL2/IFNG ≥ 1 and a normal liver biopsy underwent immunosuppression (IS) withdrawal. The primary end point was the development of operational tolerance. Secondary end points included correlation of tolerance with allograft gene expression and immune cell markers. Twenty-eight of 69 patients (38%) were positive for the PBMC tolerance biomarker and 23 proceeded to IS withdrawal. Nine of the 23 patients had abnormal baseline liver biopsies and were excluded. Of the 14 patients with normal biopsies, eight (57%) have achieved operational tolerance and are off IS (range 12-57 months). Additional studies revealed that all of the tolerant patients and only one non-tolerant patient had a liver gene ratio of FOXP3/IFNG ≥ 1 prior to IS withdrawal. Increased CD4+ T regulatory T cells were detected both in PBMC and livers of tolerant patients following IS withdrawal. Higher expression of SELE (gene for E-selectin) and lower expression of genes associated with inflammatory responses (GZMB, CIITA, UBD, LSP1, and CXCL9) were observed in the pre-withdrawal liver biopsies of tolerant patients by RNA sequencing. These results suggest that measurement of PBMC FGL2/IFNG may enrich for the identification of operationally tolerant liver transplant patients, especially when combined with intragraft measurement of FOXP3/IFNG. Clinical Trial Registration: ClinicalTrials.gov (LITMUS: NCT02541916)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Maternal and cord blood collected from 33 Nigerian mother-child pairs were tested for measles-sepcific IgG. All 33 had protective measles antibodies at the time of delivery with a positive correlation of r = 0.87. Determination of the rate of waning of these antibodies revealed that 58 per cent of these children had lost the protective maternal antibody by the age of 4 months and only 3 per cent of the children had enough antibody to protect them between the ages of 6-9 months. Fifty-five colostrum samples from the same mothers and 347 breastmilk samples collected at various periods of breastfeeding also showed that anti-measles IgA had dropped below the protective cut-off within the first 2 weeks of birth. It is evident that the Nigerian child is born with solid anti-measles antibody but the rate of waning has left a large number unprotected before the first dose of the vaccine. There is an urgent need to review the measles vaccination programme in Nigeria to protect these susceptible infants.