Serum and tissue biomarkers of plasma-cell rich rejection in liver transplant recipients.

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 under-recognized 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, necro-inflammation, 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. Herein is a literature review of candidate serum 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.

Clinicopathological and immunohistochemical analysis of plasma cell-rich rejection in renal transplantation: Involvement of intratubular Th1/Th2 balance in plasma cell enrichment.

AIM: Plasma cell-rich rejection (PCRR) has been considered a subtype of acute T-cell-mediated rejection (ATCR). However, PCRR is recognized as refractory rejection and different from ATCR in various ways. In order to elucidate the pathogenesis of PCRR, we analysed PCRR clinicopathologically and immunohistochemically by comparing it with ATCR. METHODS: Twelve cases of PCRR (PCRRs) and 22 cases of usual ATCR (ATCRs) diagnosed at our hospital between January 2008 and March 2017 were included. Between PCRRs and ATCRs, we compared clinical data, Banff classification, graft outcome and the total sum number of T-bet- and GATA3-positive lymphocytes infiltrating in tubular epithelium using immunohistochemistry. RESULTS: Plasma cell-rich rejections occurred later than ATCRs (median time after transplantation 1340.5 days vs. 52.5 days). Serum creatinine levels at discharge after treatment were significantly higher in PCRRs than in ATCRs (median 2.38 vs. 1.65 mg/dL). Cumulative rate of graft loss was significantly higher in PCRRs than in ATCRs (1-, 2- and 5-year: 26.7%, 51.1% and 51.1% vs. 0%, 0% and 17.5%). For profiles of Th1 and Th2, we found significantly lower ratio of T-bet/GATA3-positive lymphocytes in PCRRs compared with ATCRs. CONCLUSION: This study suggests that PCRR is more refractory than ATCR and there are significant differences in populations of helper T-cell subsets between them. We consider helper T-cell subset analysis valuable for developing new treatment strategies for PCRR.

A suspected case of plasma cell-rich acute renal transplant rejection associated with de novo donor-specific antibody.

A kidney transplant case with de novo donor-specific antibody showed monoclonal plasma cell infiltration into the graft with ABO incompatibility. Three years after transplantation, the patient's graft function suddenly deteriorated. Interstitial edema and the predominant infiltration of inflammatory plasma cells with kappa chain monoclonality were observed in biopsy specimens. The in situ hybridization of Epstein-Barr virus was negative and post-transplant lymphoproliferative disorder was not evident from radiological examinations. On laboratory examination, the patient had de novo donor-specific antibody for HLA-DQ. We suspected plasma cell-rich acute rejection for which methylprednisolone pulse therapy, plasma exchange, rituximab, and 15-deoxyspergualin were given. In the ensuing biopsy, the degree of plasma cell infiltration was similar to the first biopsy; however, kappa chain monoclonality relatively weakened. Owing to resistance to these treatments, intravenous immunoglobulin (IVIG) (0.5 g/kg/day) was added. The serum creatinine level gradually declined to 3.1 mg/dL; however, it increased up to 3.6 mg/dL again. In the final biopsy, the infiltrated plasma cells disappeared but severe interstitial fibrosis developed. This case showed difficulty in the diagnosis and treatment of plasma cell-rich acute rejection. A detailed consideration of this case may be helpful in understanding the clinical features and pathogenesis of this condition.

Plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation.

We report a case of plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. A 33-year-old man was admitted for an episode biopsy; he had a serum creatinine (S-Cr) level of 5.7 mg/dL 1 year following primary kidney transplantation. Histological features included two distinct entities: (1) a focal, aggressive tubulointerstitial inflammatory cell (predominantly plasma cells) infiltration with moderate tubulitis; and (2) inflammatory cell infiltration (including neutrophils) in peritubular capillaries. Substantial laboratory examination showed that the patient had donor-specific antibodies for DQ4 and DQ6. Considering both the histological and laboratory findings, we diagnosed him with plasma cell-rich rejection accompanied by acute antibody-mediated rejection. We started 3 days of consecutive steroid pulse therapy three times every 2 weeks for the former and plasma exchange with intravenous immunoglobulin (IVIG) for the latter histological feature. One month after treatment, a second allograft biopsy showed excellent responses to treatment for plasma cell-rich rejection, but moderate, acute antibody-mediated rejection remained. Therefore, we added plasma exchange with IVIG again. After treatment, allograft function was stable, with an S-Cr level of 2.8 mg/dL. This case report demonstrates the difficulty of the diagnosis of, and treatment for, plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. We also include a review of the related literature.

Late-Onset Rejection in Liver Allograft Biopsies: An Analysis of Process, Pattern, and Clinical Implications.

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.

IgG4 plasma cell neoplasm in liver transplant biopsy masquerading as rejection.

IgG4 plasma cell neoplasm and myeloma are rare disease entities, not associated with systemic fibroinflammatory IgG4 related disease. We herein present a case of IgG4 plasma cell neoplasm in a liver transplant biopsy. A 55 year old female was treated with living donor transplant and had a complicated post-operative course. Three months post-transplant, she presented with small for size syndrome, biliary stricture, and inferior vena cava stenosis. Concomitant liver biopsy revealed mild acute cellular rejection with central perivenulitis pattern, and mild centrilobular fibrosis. She was treated with steroids which resulted in improvement of liver enzymes. Seven months post-transplant, she presented with subtherapeutic prograf levels and cholestatic pattern of elevated liver tests. ERCP revealed a stone which was removed. Hematological evaluation revealed an abnormal serum protein electrophoresis (SPEP). Monoclonal IgG kappa was elevated along with mildly elevated free Kappa/Lambda ratio. She was followed up and readmitted two months later for worsening liver function tests. The liver biopsy showed monotypic Kappa-and IgG4-restricted plasma cell infiltrates in portal, periportal, sinusoidal and centrilobular regions, compatible with plasma cell neoplasm. In the clinical context of positivity for a serum M-spike, the monoclonal hepatic infiltrates were deemed consistent with a Kappa-and IgG4-restricted plasma cell neoplasm. Patient was treated with pulsed steroids, and liver function tests subsequently downtrended. She was followed up by Hemoncology, and the treatment plan included carfilzomib-based induction therapy and dexamethasone to prevent end-organ damage from evolving myeloma. In the meanwhile, she developed acute appendicitis, underwent appendectomy, and passed away in the post-operative period.

Histologic and Clinical Outcomes of Patients Developing Post-Liver Transplant Plasma Cell-Rich Rejection.

OBJECTIVES: Plasma cell-rich rejection (PCCR), also known as "plasma cell hepatitis" or "de novo autoimmune hepatitis," is a cause of allograft dysfunction occurring post-liver transplantation (LT). Patients often develop allograft failure and may require repeat LT. PCRR may fall within the spectrum of different histologies associated with antibody-mediated rejection (AMR), which is associated with donor-specific antibodies (DSAs) and positive complement component C4 (C4d) immunostaining. We sought to analyze the histologic and clinical outcomes of patients having biopsy-proven PCRR as well as to examine its C4d staining and DSA profiles. METHODS: We identified patients having PCRR between 2000 and 2020 using the electronic pathology database at our institution. We included patients who underwent at least one follow-up liver biopsy after establishing the PCRR diagnosis to assess future histologic progression and outcomes. Mean fluorescence intensity for at least one single DSA of 2,000 or higher was considered positive. Histologic diagnosis of PCRR was independently made by an experienced liver pathologist. RESULTS: A total of 35 patients were included in the study. Hepatitis C virus was the most common etiology for LT (59.5%). Mean ± SD age at LT was 49.0 ± 12.7 years. Forty percent of patients developed PCRR within 2 years of LT. Most patients (68.5%) had negative outcomes, with progression from PCRR to cirrhosis or chronic ductopenic rejection (CDR). Patients who had hepatitis C virus were more likely to develop cirrhosis rather than CDR following the PCRR diagnosis (P = .01). Twenty-three (65.7%) patients had at least one prior episode of T-cell-mediated rejection before being diagnosed with PCRR. DSAs were positive in 16 of 19 patients assessed, and C4d immunostaining was positive in 9 of 10 patients. CONCLUSIONS: Development of PCRR negatively affects liver allograft outcomes and patient survival after LT. The presence of DSA and C4d in PCRR patients supports it to be within the histologic spectrum of AMR.

Rethinking de novo immune hepatitis, an old concept for liver allograft rejection: Relevance of glutathione S-transferase T1 mismatch.

Antibody-mediated rejection (AMR) in liver transplantation has long been underestimated. The concept of the liver as an organ susceptible to AMR has emerged in recent years, not only in the context of the major histocompatibility complex with the presence of HLA donor-specific antibodies, but also with antigens regarded as "minor", whose role in AMR has been demonstrated. Among them, antibodies against glutathione S-transferase T1 have been found in 100% of patients with de novo autoimmune hepatitis (dnAIH) when studied. In its latest update, the Banff Working Group for liver allograft pathology proposed replacing the term dnAIH with plasma cell (PC)-rich rejection. Antibodies to glutathione S-transferase T1 (GSTT1) in null recipients of GSTT1 positive donors have been included as a contributory but nonessential feature of the diagnosis of PC-rich rejection. Also in this update, non-organ-specific anti-nuclear or smooth muscle autoantibodies are no longer included as diagnostic criteria. Although initially found in a proportion of patients with PC-rich rejection, the presence of autoantibodies is misleading since they are not disease-specific and appear in many different contexts as bystanders. The cellular types and proportions of the inflammatory infiltrates in diagnostic biopsies have been studied in detail very recently. PC-rich rejection biopsies present a characteristic cellular profile with a predominance of T lymphocytes and a high proportion of PCs, close to 30%, of which 16.48% are IgG4+. New data on the relevance of GSTT1-specific T lymphocytes to PC-rich rejection will be discussed in this review.

Rituximab in the treatment of refractory late acute antibody-mediated rejection: Our initial experience.

Antibody-mediated rejection (AMR) is not uncommon after renal transplantation and is harder to handle compared to cell-mediated rejection. When refractory to conventional therapies, rituximab is an attractive option. This study aims to examine the effectiveness of rituximab in refractory late acute AMR. This is a retrospective study involving nine renal transplant recipients. Four doses of rituximab were administered at weekly interval for 4 weeks, at a dose of 375 mg/m2. The mean age of patients was 35.3 ± 7.38 years. The median period between transplantation and graft dysfunction was 30 ± 20 months. Mean serum creatinine at the time of discharge after transplantation and at the time of acute AMR diagnosis was 1.14 ± 0.19 mg/dl and 2.26 ± 0.57 mg/dl, respectively. After standard therapy, it was 2.68 ± 0.62 mg/dl. One patient died of Pseudomonas sepsis and three patients progressed to end-stage renal disease (ESRD). Four biopsies showed significant plasma cell infiltrations. Mean serum creatinine among non-ESRD patients at the end of 1 year progressed from 2.3 ± 0.4 to 3.8 ± 1.2 mg/dl (P value 0.04). eGFR prior to therapy and at the end of 1 year were 34.4 ± 6.18 and 20.8 ± 7.69 ml/min (P value 0.04), respectively. Only one patient showed improvement in graft function in whom donor-specific antibody (DSA) titers showed significant improvement. Rituximab may not be effective in late acute AMR unlike in early acute AMR. Monitoring of DSA has a prognostic role in these patients and plasma cell rich rejection is associated with poor prognosis.