Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation.

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.

Genetic architecture underlying IgG-RF production is distinct from that of IgM-RF.

OBJECTIVE: HLA-DRB1 alleles, particularly the shared epitope (SE) alleles, are strongly associated with RA. Different genetic structures underlie the production of the various autoantibodies in RA. While extensive genetic analyses have been conducted to generate a detailed profile of ACPA, a representative autoantibody in RA, the genetic architecture underlying subfractions of RF other than IgM-RF, namely IgG-RF, known to be associated with rheumatoid vasculitis, is not well understood. METHODS: We enrolled a total of 743 RA subjects whose detailed autoantibody (IgG-RF, IgM-RF, and ACPA) data were available. We evaluated co-presence and correlations of the levels of these autoantibodies. We analysed associations between the presence or levels of the autoantibodies and HLA-DRB1 alleles for the 743 RA patients and 2008 healthy controls. RESULTS: We found both IgG-RF(+) and IgG-RF(-) RA subjects showed comparable associations with SE alleles, which was not observed for the other autoantibodies. Furthermore, there was a clear difference in SE allele associations between IgG-RF(+) and (-) subsets: the association with the IgG-RF(+) subsets was solely driven by HLA-DRB1*04:05, the most frequent SE allele in the Japanese population, while not only HLA-DRB1*04:05 but also HLA-DRB1*04:01, less frequent in the Japanese population but the most frequent SE allele in Europeans, were main drivers of the association in the IgG-RF(-) subset. We confirmed that these associations were irrespective of ACPA presence. CONCLUSION: We found a unique genetic architecture for IgG-RF(-) RA, which showed a strong association with a SE allele not frequent in the Japanese population but the most frequent SE allele in Europeans. The findings could shed light on uncovered RA pathology.

The impact of human leukocyte antigen mismatch on recipient outcomes in living-donor liver transplantation.

Donor-recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990-2020). The primary and secondary endpoints were recipient survival and the incidence of T cell-mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0-10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and <0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21-5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11-5.35; p = 0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor-recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children.

Donor-dominant one-way matching of human leukocyte antigen-A/B/DR alleles predicts graft-versus-host disease following living donor liver transplantation.

AIM: Graft-versus-host disease (GVHD) following liver transplantation is rare but fatal. Therefore, it is important to identify possible risk factors before transplantation. Although it has been suggested that donor-dominant one-way human leukocyte antigen (HLA) matching of three loci (HLA-A/B/DR) is associated with the occurrence of GVHD, the precise significance of HLA matching including HLA-C/DQ/DP remains unclear. METHODS: We retrospectively analyzed the impact of donor-dominant one-way HLA matching at six HLA loci at the allele level on GVHD using clinical registry data from 1759 cases who underwent living donor liver transplantation between June 1990 and June 2019. We extracted cases with donor-dominant one-way HLA matching at the antigen level and reconfirmed them at the allele level using preserved DNA samples. RESULTS: Three of four cases (75%) who developed GVHD showed donor-dominant one-way HLA matching at three HLA-A/B/DR loci. These cases also showed donor-dominant one-way HLA matching at HLA-C/DQ/DP. Three of six cases (50%) with donor-dominant one-way HLA matching at three loci of HLA-A/B/DR developed GVHD. Notably, none of the cases with donor-dominant one-way HLA matching at one or two HLA-A/B/DR loci developed GVHD, irrespective of matching status at HLA-C/DQ/DP. The HLA matching status at the antigen level was revised in 22 of 56 cases, following reconfirmation at the allele level. CONCLUSIONS: Pairing of donors and recipients with donor-dominant one-way HLA matching at three HLA-A/B/DR loci should be avoided to prevent GVHD. No impact of HLA-C/DQ/DP on GVHD was identified. For liver transplantation, HLA genotypes should be determined at the allele level.

[Small B-cell neoplasm responding to ibrutinib after 17 years of cold agglutinin disease symptom].

In this study, we report a case of a 77-year-old woman who was presented with anemia in the winter of 2002. She was diagnosed with cold agglutinin disease (CAD) and treated with corticosteroids. Further, her hemoglobin levels were maintained between 7.0 g/dl and 8.0 g/dl. In May 2019, mature peripheral blood lymphocytes increased with exacerbation of hemolytic anemia. The lymphocytes were positive for CD19 and CD20, but negative for CD5, CD10, and CD23. Additionally, they were positive for cell surface IgM-κ. The B-cell neoplasm could not be further subclassified due to the lack of BCL2-IgH and BCL1-IgH rearrangement and morphology. The IgM-κ-type M-protein was found in serum, and the direct Coombs test was negative for IgG but positive for C3b/C3d. These findings suggested that small B-cell neoplasm-associated M-protein was involved in the development of CAD through complement activation. Based on the presence of TP53 deletion, the patient was treated with ibrutinib monotherapy. Although hemolysis rapidly improved with a dramatic decrease in lymphocytes, she died from a cerebral hemorrhage. It is assumed that ibrutinib improved CAD through suppression of small B-cell neoplasm-related M-protein. CAD can precede lymphoproliferative disorders; however, the risk of ibrutinib-associated hemorrhage should be noted.

Erythrocyte Alloimmunity and Genetic Variance: Results from the Collaborative Study of Alloimmunity to Antigen Diversity in Asian Populations (All ADP).

As an East-Asian international study, we evaluated erythrocyte alloimmunity by gender and history of transfusion or pregnancy. In total, data from more than 1,826,000 patients were analyzed, from whom 26,170 irregular erythrocyte antibodies were detected in 22,653 cases. Antibody frequencies in these cases were as follows: anti-E, 26.8%; anti-Lea, 20.0%; anti-P1, 7.1%; anti-M, 6.4%; anti-Mia, 5.6%; anti-c + E, 5.6%; anti-Leb, 4.6%; anti-D, 2.8%; anti-Fyb, 2.6%; anti-Lea+Leb, 2.5%; anti-Dia, 2.0%; and others. For pregnant patients, anti-D (12.7%) was statistically more frequent. For transfused patients, anti-E (37.3%), anti-c + E (9.5%), anti-C + e (3.3%) and anti-Jka (3.1%) were significantly more frequent.

Two susceptibility loci to Takayasu arteritis reveal a synergistic role of the IL12B and HLA-B regions in a Japanese population.

Takayasu arteritis (TAK) is an autoimmune systemic vasculitis of unknown etiology. Although previous studies have revealed that HLA-B*52:01 has an effect on TAK susceptibility, no other genetic determinants have been established so far. Here, we performed genome scanning of 167 TAK cases and 663 healthy controls via Illumina Infinium Human Exome BeadChip arrays, followed by a replication study consisting of 212 TAK cases and 1,322 controls. As a result, we found that the IL12B region on chromosome 5 (rs6871626, overall p = 1.7 × 10(-13), OR = 1.75, 95% CI 1.42-2.16) and the MLX region on chromosome 17 (rs665268, overall p = 5.2 × 10(-7), OR = 1.50, 95% CI 1.28-1.76) as well as the HLA-B region (rs9263739, a proxy of HLA-B*52:01, overall p = 2.8 × 10(-21), OR = 2.44, 95% CI 2.03-2.93) exhibited significant associations. A significant synergistic effect of rs6871626 and rs9263739 was found with a relative excess risk of 3.45, attributable proportion of 0.58, and synergy index of 3.24 (p ≤ 0.00028) in addition to a suggestive synergistic effect between rs665268 and rs926379 (p ≤ 0.027). We also found that rs6871626 showed a significant association with clinical manifestations of TAK, including increased risk and severity of aortic regurgitation, a representative severe complication of TAK. Detection of these susceptibility loci will provide new insights to the basic mechanisms of TAK pathogenesis. Our findings indicate that IL12B plays a fundamental role on the pathophysiology of TAK in combination with HLA-B(∗)52:01 and that common autoimmune mechanisms underlie the pathology of TAK and other autoimmune disorders such as psoriasis and inflammatory bowel diseases in which IL12B is involved as a genetic predisposing factor.

Genotyping of relapsing polychondritis identified novel susceptibility HLA alleles and distinct genetic characteristics from other rheumatic diseases.

OBJECTIVE: To uncover the genetic background of relapsing polychondritis (RPC), a rare autoimmune disease with unknown mechanisms characterized by systemic inflammation of the cartilage, to deepen our understanding of the pathophysiology of RPC and show its distinct genetic characteristics from other rheumatic diseases. METHODS: A total of 102 patients with RPC and 1000 healthy subjects were recruited for a two-staged genetic association study and genotyped for six HLA classical loci. Haplotype association tests were also performed. The associations of amino acid (AA) residues and positions with susceptibility to RPC were analysed. Frequencies of representative susceptibility HLA alleles to other rheumatic diseases in RPC were also analysed. RESULTS: HLA-DRB1*16:02, HLA-DQB1*05:02 and HLA-B*67:01, which are in linkage disequilibrium with each other, were associated with RPC (P = 1.9 × 10(-6), 1.4 × 10(-5) and 0.00024, respectively). AA residue at position 57 in HLA-DQB1, the most significant position in type I diabetes mellitus, showed the strongest association among AA residues. HLA-DR4, a known susceptibility allele in Germans, showed a trend of susceptibility association without significance (P = 0.067). No associations were observed between the three alleles and clinical phenotypes. Representative susceptibility HLA alleles to RA, SLE, Behçet disease and Takayasu arteritis did not show enrichment in RPC in spite of sufficient statistical power. CONCLUSIONS: HLA-DRB1*16:02, HLA-DQB1*05:02 and HLA-B*67:01, in linkage disequilibrium with each other, are associated with susceptibility to RPC Importance of HLA-class II loci in RPC susceptibility is suggested. RPC is considered a genetically distinct disease from other rheumatic diseases.

Periomphalitis with Delayed Umbilical Cord Separation due to Alloimmune Neonatal Neutropenia.

In a preterm infant, small-for-gestational age, neutropenia persisted from the birth, and periomphalitis symptoms appeared at 23 days of age. Upon administration of granulocyte colony-stimulating factor, the neutrophil count increased, and periomphalitis was recovered. At the same time, the umbilical cord separated at 44 days of age. The human neutrophil antigen (HNA) of the infant was 1a/1b, and antineutrophil antibody for HNA-1b was present in both serums of the mother and the infant at birth, indicating a diagnosis of alloimmune neutropenia. This case demonstrated a definite relationship between the number of neutrophils and the separation of umbilical cord.

Application of complement component 4d immunohistochemistry to ABO-compatible and ABO-incompatible liver transplantation.

Antibody-mediated rejection (AMR) is difficult to diagnose after ABO-compatible or ABO-identical (ABO-C) liver transplantation. To determine whether complement component 4d (C4d) immunostaining would be useful for diagnosing AMR, we compared the results of C4d immunohistochemistry for allograft biopsy samples with assays for anti-donor antibodies performed at the time of biopsy. One hundred fourteen patients with ABO-C grafts and 29 patients with ABO-incompatible (ABO-I) grafts were included. Linear C4d endothelial staining (identifiable with a 4× objective lens) or staining seen in 50% or more of the portal tracts was considered positive. Five of the 114 patients (4%) with ABO-C grafts and 15 of the 29 patients (52%) with ABO-I grafts showed C4d positivity. In the ABO-C cases, C4d positivity in late biopsy samples (≥30 days after transplantation) was associated with stage 2 or higher fibrosis (METAVIR score; P = 0.01) and with the presence of donor-specific anti-human leukocyte antigen DR antibodies (HLA-DR DSAs) with a mean fluorescence intensity > 5000 according to the Luminex single-antigen bead assay (P = 0.04). Conversely, the presence of HLA-DR DSAs was associated with the presence of stage 2 or higher fibrosis, acute cellular rejection, and C4d positivity. During the 2-year follow-up, neither C4d positivity nor HLA-DR DSAs were related to graft loss. Among ABO-I patients, C4d positivity was not associated with allograft dysfunction or fibrosis. Only 3 of the 15 C4d-positive patients (20%) showed periportal hemorrhagic edema, which could be a histological sign of AMR in ABO-I grafts, and they were the only cases associated with elevations in anti-donor A/B antibody titers. In conclusion, C4d endothelial positivity among ABO-C patients is an uncommon event that could be associated with chronic graft damage with or without clinical AMR. C4d positivity is common among ABO-I patients and may not be associated with allograft dysfunction if alloantibody titers are not elevated.

Redo living-donor lobar lung transplantation for bronchiolitis obliterans associated with antibody-mediated rejection.

Living-donor lobar lung transplantation (LDLLT) is an established therapy for patients with end-stage lung disease, but living-donor lobar lung retransplantation (re-LDLLT) is rarely reported. We previously reported a case of unilateral antibody-mediated rejection after LDLLT in the presence of newly formed donor-specific antibodies against a right-lobe donor. The same patient developed contralateral bronchiolitis obliterans, resulting in bilateral bronchiolitis obliterans, but re-LDLLT was successful. Pathological findings of the explanted lungs were consistent with the clinical course of the patient. One year after re-LDLLT, the patient is doing well without any anti-human leukocyte antigen antibodies. Four lobes from four different donors were transplanted in this patient. The first two lobes were rejected eventually, but the two lobes implanted later presented no signs of rejection at least for 1 year after the transplant. Herein, we report this rare case and compare the clinical course and pathological findings.

Surface chemical approach to single-step measurement of antibody in human serum using localized surface plasmon resonance biosensor on microtiter plate system.

In clinical settings, serum antibody levels serve as markers of pathology. For example, antibodies related to autoimmune diseases are among the conventional targets in laboratory tests. Simple clinical tests can improve the efficacy of laboratory practice. This study describes a single-step, wash-free technique for optically detecting antibodies in human serum through the localized surface plasmon resonance (LSPR) of gold nanoparticles. As a proof-of-concept experiment, the amount of antibiotin dissolved in human serum was measured with a LSPR-based biosensor in a wash-free manner using a conventional 96-well microtiter plate and a plate reader. For an efficient surface modification of biosensors, zwitterionic copolymer was used as a scaffold on the gold nanoparticle surface to immobilize antigen and blocking reagent. Single-step, wash-free measurement of antibiotin in human serum was successfully achieved. In addition, nonspecific responses from serum contents were significantly reduced because both the copolymer and hydrophilic antigen reagent that we employed were composed of poly(ethylene oxide) spacer. Comparative experiments of the antigen-antibody reaction in serum to that in buffered solution revealed that serum is a favorable environment for the biological reaction. In conclusion, our gold-nanoparticle-based LSPR method may provide a rapid and simple way to measure the amount of antibody in serum quantitatively in clinical practice.

The protective association of HLA-C*12:02 and HLA-DQB1*06:01 with severe acute hepatitis of unknown origin in the Japanese population.

Global surveillance has been conducted to elucidate the pathogenesis of acute hepatitis of unknown origin (AHUO), However, the factors associated with the aggravation of this serious disease are unclear. Therefore, we conducted a HLA association study to identify HLA alleles or haplotypes predisposing or protective against Japanese AHUO. The HLA 5 locus (HLA-A, HLA-B, C, DRB1, and DQB1) 4-digit genotyping results of 72 AHUO patients who underwent liver transplantation at our institution between 2000 and 2021 were compared to those of 873 healthy Japanese controls. Protective associations of HLA-B*52:01 (p-corrected (pc) = 3.15 × 10-3 ), HLA-C*12:02 (pc = 1.66 ×10-3 ), HLA-DQB1*06:01 (pc = 1.42 × 10-2 ), and HLA-DRB1*15:02 (pc = 1.36 × 10-2 ) with severe AHUO in Japanese patients were observed. The amino acid residues of tryptophan at position 156, which are located in the antigen-binding grooves of the HLA-C protein, showed a protective association with AHUO, showing a significant difference from other amino acid variations (pc = 9.0 × 10-4 ). Furthermore, 5 amino acid residues of the HLA-DQB1 protein were also protectively associated with AHUO with a significant difference from other amino acid variations (pc = 1.42 × 10-2 to 2.89 × 10-2 ). These alleles have a protective association with the aggravation of AHUO in the Japanese population.

Association of Takayasu arteritis with HLA-B 67:01 and two amino acids in HLA-B protein.

OBJECTIVE: Takayasu arteritis (TAK) is a rare autoimmune arteritis that affects large arteries. Although the association between TAK and HLA-B 52:01 is established, the other susceptibility HLA-B alleles are not fully known. We performed genetic association studies to determine independent HLA-B susceptibility alleles other than HLA-B 52:01 and to identify important amino acids of HLA-B protein in TAK susceptibility. METHODS: One hundred patients with TAK and 1000 unrelated healthy controls were genotyped for HLA-B alleles in the first set, followed by a replication set containing 73 patients with TAK and 1000 controls to compare the frequencies of HLA-B alleles. Step-up logistic regression analysis was performed to identify susceptibility amino acids of HLA-B protein. RESULTS: Strong associations of susceptibility to TAK with HLA-B 52:01 and HLA-B 67:01 were observed (P = 1.0 × 10(-16) and 9.5 × 10(-6), respectively). An independent susceptibility effect of HLA-B 67:01 from HLA-B 52:01 was also detected (P = 1.8 × 10(-7)). Amino acid residues of histidine at position 171 and phenylalanine at position 67, both of which are located in antigen binding grooves of the HLA-B protein, were associated with TAK susceptibility (P ≤ 3.8 × 10(-5)) with a significant difference from other amino acid variations (ΔAIC ≥ 9.65). CONCLUSION: HLA-B 67:01 is associated with TAK independently from HLA-B 52:01. Two amino acids in HLA-B protein are strongly associated with TAK susceptibility.

Significance of semiquantitative assessment of preformed donor-specific antibody using luminex single bead assay in living related liver transplantation.

AIM: To analyze the risks of preoperatively produced donor-specific antibody (DSA) in liver transplantation. METHODS: DSA was assessed using direct complement-dependent cytotoxicity (CDC) and anti-human globulin- (AHG-) CDC tests, as well as the Luminex Single Antigen assay. Among 616 patients undergoing blood type identical or compatible living donor liver transplantation (LDLT), 21 patients were positive for CDC or AHG-CDC tests, and the preserved serum from 18 patients was examined to determine targeted Class I and II antigens. The relationships between the mean fluorescence intensity (MFI) of DSA and the clinical outcomes were analyzed. RESULTS: Patients were divided into 3 groups according to the MFI of anti-Class I DSA: high (11 patients with MFI > 10,000), low (2 patients with MFI < 10,000), and negative (5 patients) MFI groups. Six of 11 patients with high Class-I DSA showed positive Class-II DSA. Hospital death occurred in 7 patients of the high MFI group. High MFI was a significant risk factor for mortality (P = 0.0155). Univariate analysis showed a significant correlation between MFI strength and C4d deposition (P = 0.0498). CONCLUSIONS: HLA Class I DSA with MFI > 10,000 had a significant negative effect on the clinical outcome of patients with preformed DSA in LDLT.

Incidence and pattern of hemolytic anemia after minor ABO-mismatched living-donor lobar lung transplantation.

PURPOSE: Living-donor lobar lung transplantation (LDLLT) has been successfully performed in Japan. In LDLLT, the recipient usually receives one lower lobe from each of two donors; however, finding two ABO-matched donors is often difficult. Solid organ transplants from donors with minor ABO-mismatches can be complicated by hemolysis. We investigated the incidence of de novo anti-ABO antibody production and hemolysis in patients receiving LDLLT across minor ABO-mismatches. METHODS: We evaluated 23 patients who underwent LDLLT between June 2008 and December 2011, including 11 patients who underwent minor ABO-mismatched transplantation. We measured the anti-A/B antibody serum titers, hemoglobin concentrations and indirect bilirubin levels. RESULTS: None of the patients showed any clinical signs of hemolytic anemia (mean follow-up period; 16 months). Two of the 11 patients (18 %) receiving minor ABO-mismatched LDLLTs showed a small amount of de novo anti-B antibodies for a transient period. These patients showed gradual progression of anemia, and weak de novo anti-A/B antibodies were detected with column agglutination technology. The patients received only 2 U of washed type O red blood cells; thereafter, the hemolytic anemia did not develop further in either case. CONCLUSION: LDLLT across minor ABO-mismatches results in the transient appearance of weak de novo anti-A/B antibodies with a low incidence; thus, this procedure can be a safe treatment.

Impact of Spousal Donation on Postoperative Outcomes of Living-donor Lobar Lung Transplantation.

BACKGROUND: The effect of human leukocyte antigen mismatches between donors and recipients on postoperative outcomes of lung transplantation remains controversial. We retrospectively reviewed adult recipients receiving living-donor lobar lung transplantation (LDLLT) to examine the difference in de novo donor-specific antibody (dnDSA) development and clinically diagnosed unilateral chronic lung allograft dysfunction per graft (unilateral CLAD) between lung grafts donated by spouses (nonblood relatives) and nonspouses (relatives within the third degree). We also investigated the difference in prognoses between recipients undergoing LDLLTs including spouse donors (spousal LDLLTs) and not including spouse donors (nonspousal LDLLTs). METHODS: In this study, 63 adult recipients undergoing LDLLTs (61 bilateral and 2 unilateral LDLLTs from 124 living donors) between 2008 and 2020 were enrolled. The cumulative incidence of dnDSAs per lung graft was calculated, and prognoses were compared between recipients undergoing spousal and nonspousal LDLLTs. RESULTS: The cumulative incidence of both dnDSAs and unilateral CLAD in grafts donated by spouses was significantly higher than that in grafts donated by nonspouses (5-y incidence of dnDSAs: 18.7% versus 6.4%, P = 0.038; 5-y incidence of unilateral CLAD: 45.6% versus 19.4%, P = 0.011). However, there were no significant differences in the overall survival or chronic lung allograft dysfunction-free survival between recipients undergoing spousal and nonspousal LDLLTs ( P > 0.99 and P = 0.434, respectively). CONCLUSIONS: Although there were no significant differences in prognoses between spousal and nonspousal LDLLTs, more attention should be paid to spousal LDLLTs because of the higher development rate of dnDSAs and unilateral CLAD.

An adult case of refractory autoimmune neutropenia after liver transplantation.

Autoimmune neutropenia (AIN) is an exceptionally rare condition that occurs after liver transplantation. Here, we report an adult case of refractory AIN 3.5 years after liver transplantation. A 59-year-old man who underwent brain-dead donor liver transplantation in August 2018 developed rapid neutropenia (0.07 × 109/L) in December 2021. The patient was diagnosed with AIN based on positivity for anti-human neutrophil antigen-1a antibody. There was no response to granulocyte colony-stimulating factor (G-CSF), prednisolone, or rituximab, and intravenous immunoglobulin (IVIg) therapy induced only a temporary recovery in neutrophil count. The patient continued to have a low neutrophil count for several months. However, the response to IVIg and G-CSF improved after the post-transplant immunosuppressant was changed from tacrolimus to cyclosporine. Post-transplant AIN has many unknown aspects. Tacrolimus-induced immunomodulation and graft-associated alloimmunity may be involved in its pathogenesis. Further studies are needed to elucidate the underlying mechanisms and explore new treatment options.

Progressive graft fibrosis and donor-specific human leukocyte antigen antibodies in pediatric late liver allografts.

The role of donor-specific anti-human leukocyte antigen antibodies (DSAs) that develop late after living donor liver transplantation is unknown. Seventy-nine pediatric recipients who had good graft function and underwent protocol liver biopsy more than 5 years after transplantation (median = 11 years, range = 5-20 years) were reviewed. DSAs were determined with the Luminex single-antigen bead assay at the time of the last biopsy, and complement component 4d (C4d) immunostaining was assessed at the times of the last biopsy and the previous biopsy. The donor specificity of antibodies could be identified in 67 patients: DSAs were detected in 32 patients (48%), and they were usually against human leukocyte antigen class II (30 cases) but were rarely against class I (2 cases). These patients had a higher frequency of bridging fibrosis or cirrhosis (28/32 or 88%) than DSA-negative patients (6/35 or 17%, P < 0.001). Fibrosis was likely to be centrilobular-based. DSA-positive patients, in comparison with DSA-negative patients, had higher frequencies of diffuse/focal endothelial C4d staining (P < 0.001) and mild/indeterminate acute rejection [15/32 (47%) versus 5/35 (14%), P = 0.004]. Four DSA-negative patients were off immunosuppression, whereas no patients in the DSA-positive group were (P = 0.048). In conclusion, the high prevalence of graft fibrosis and anti-class II DSAs in late protocol biopsy samples suggests that humoral alloreactivity may contribute to the process of unexplained graft fibrosis late after liver transplantation.