Antibodies In Liver Transplantation Research Articles

Donor-specific antibodies in liver transplantation: challenges in diagnosis and determining clinical impact.

Our understanding of the clinical impact of donor-specific antibodies in liver transplant recipients has evolved in recent years as outcomes for liver allografts have improved and advances in diagnostic testing have made recognition of antibody mediated rejection in transplant patients more sensitive. Two main types of donor-specific antibodies - preformed and de novo - have been reported in the literature to have a negative impact on graft survival, and researchers have been able to further identify subclasses of class II donor-specific antibodies as being the most clinically impactful. Furthermore, there is evidence that donor-specific antibody formation can augment cellular rejection in liver grafts and lead to worsened clinical outcomes. Recent data have shown a higher prevalence of donor-specific antibody formation than previously reported. This review explores the most recent literature regarding the clinical impact of both preformed and de-novo donor-specific antibodies and potential management guidelines for patients undergoing liver transplantation. The best practice guidelines for undergoing monitoring for donor-specific antibody formation and protocol biopsies in sensitized patients will depend on further multiinstitutional studies.

Effects of re-augmenting maintenance immunosuppression on post-transplant donor-specific HLA antibodies in liver transplantation

BackgroundDonor-specific antibodies (DSAs) have various negative short- and long-term effects after organ transplantation. DSAs are prevalent in patients with insufficient immunosuppression; thus, even patients with stable conditions after liver transplantation should be under optimized immunosuppression. However, the effect of re-augmenting immunosuppression therapy for patients with insufficient immunosuppression remains unclear. In this study, we investigated the long-term changes and the effects of immunosuppression (IS) re-augmentation on the DSA status. MethodsTwo DSA screenings were performed in 67 patients during long-term follow-up after liver transplantation. After the first screening, IS re-augmentation was performed in patients with consent. The effects of IS re-augmentation on the DSA status were analyzed using data of the serial DSA screenings. Negative conversion was defined as DSA positivity with MFI > 1000 converted to MFI < 1000. Improvement of DSA status was defined as either a 50% reduction of MFI or negative conversion. ResultsThe median interval between the first and second DSA screening was 50 months. Among 67 patients, 43 were positive for DSAs on the first screening. Among these 43 patients, 30 had minimal to no IS therapy at the time of the first screening. Among the 30 patients, IS re-augmentation was conducted in 19. A comparison between the patients with a re-augmented IS and those with a sustained minimized IS showed that the DSA levels significantly decreased in the former (63% (12/19) vs. 18% (2/11), p = 0.02). ConclusionsThe results of this study indicate that post-liver transplant IS re-augmentation had suppressive effects on the DSA status. However, the clinical significance of DSA-negative conversion and/or mean fluorescence intensity reduction needs to be further investigated through histological evaluation and/or graft survival during longer follow-up periods.

Influence of Preformed Antibodies in Liver Transplantation.

The significance of human leukocyte antigen (HLA) matching and preformed donor-specific antibodies (DSAs) in liver transplantation remains unclear. The aim of this study was to analyze the presence of DSAs in a large cohort of 810 liver recipients undergoing liver transplant to determine the influence on acute (AR) or chronic liver rejection (CR), graft loss and allograft survival. DSAs were identified using complement dependent cytotoxicity crossmatch (CDC-CM) and multiplexed solid-phase-based flow cytometry assay (Luminex). CDC-CM showed that a 3.2% of liver transplants were positive (+CDC-CM) with an AR frequency of 19.2% which was not different from that observed in negative patients (−CDC-CM, 22.3%). Only two patients transplanted with +CDC-CM (7.6%) developed CR and suffered re-transplant. +CDC-CM patients showed a significantly lower survival rate compared to −CDC-CM patients (23.1% vs. 59.1%, p = 0.0003), developing allograft failure within the first three months (p < 0.00001). In conclusion, we have demonstrated a relationship between the presence of preformed DSAs and the low graft liver survival, indicating the important role and the potential interest of performing this analysis before liver transplantation. Our results could help to detect patients with an increased risk of graft loss, a better choice of liver receptors as well as the establishment of individualized immunosuppressive regimens.

Donor-Specific Antibodies in Liver Transplantation.

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Donor-specific antibodies in liver transplantation

Donor-specific antibodies in liver transplantation

Prevalence and Impact of Reformed and De Novo Anti-HLA Donor-Specific Antibodies in Liver Transplantation

IntroductionThe prevalence and impact of pre-existing and de novo anti-HLA donor-specific antibodies (DSAs) after orthotopic liver transplantation (OLT) is still controversial. We investigated the prevalence of DSAs and their implication in the development of allograft dysfunction after OLT. Patients and MethodsA total of 65 liver transplant patients were tested for anti-HLA antibodies, with single antigen bead technology, before, 1, 3, 6, and 12 months after transplantation, and thereafter annually, along with other risk factors. Sixteen out of 65 patients (24.6%) had circulating pre-existing anti-HLA antibodies, and 4 of them (25%) had DSAs. All patients positive for anti-HLA antibodies (100%) presented allograft dysfunction. Fourteen out of 65 patients (21.5%) had circulating de novo DSAs, and 12 out of 14 (85.7%) presented allograft dysfunction. The investigated risk factors for allograft dysfunction were: recipient and donor age, time on the waiting list, cold ischemia time, cytomegalovirus infection, immunosuppression regimen, de novo DSAs, Model for End-Stage Liver Disease, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase (GGT), direct bilirubin and total bilirubin peak post-transplant, and alkaline phosphatase. The multivariate analysis showed that de novo DSAs and time on the waiting list were independent risk factors for allograft dysfunction. ConclusionOur results show that de novo DSAs are an independent risk factor for allograft dysfunction, along with time on the waiting list.

Liver Allograft Provides Immunoprotection for the Cardiac Allograft in Combined Heart-Liver Transplantation.

When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart-liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune-mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol- and indication-specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell-mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor-specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody-mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0-0.02; p < 0.0001), antibody-mediated rejection (OR 0.04, 95% CI 0-0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07-0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients.

The impact of donor specific HLA antibody in liver transplantation

The impact of donor specific HLA antibody in liver transplantation

Utilization of Donors with Hepatitis B Core Antibodies in Liver Transplantation.

At present, the scarcity of organs is one of the major problems in transplantation. We present our own experience in expanding the acceptance criteria for deceased donors. We aimed to evaluate the potential impact of using hepatitis B virus (HBV) core antibody (anti-HBc)-positive donor grafts on the long-term liver transplantation results. We retrospectively analyzed data from 324 consecutive liver transplantation procedures performed in the largest transplant center in Poland, between January 2007 and February 2012. These patients included 36 who had received a liver from anti-HBc-positive donors. The presence of anti-HBc antibodies in the donor did not have a significant negative impact on the overall 3-year patient or graft survival rates. Among recipients with pre-transplant HBV infection, patients who received an organ from an anti-HBc-positive donor tended to have an improved survival rate compared with patients who received liver transplants from seronegative donors (p=0.080). However, there was a statistically significant reduction in graft survival (p=0.035) in the recipients without serological markers of HBV infection who received liver transplants harvested from anti-HBc-positive donors. These results confirm the validity of extending the acceptance criteria to anti-HBc-positive donors, particularly for patients with a prior HBV infection. Despite the increased risk of graft loss, liver transplantation from anti-HBc-positive donors among recipients not infected with HBV may also be considered in appropriate cases.

Clinical significance of donor-specific human leukocyte antigen antibodies in liver transplantation.

Antibody-mediated rejection (AMR) caused by donor-specific anti-human leukocyte antigen antibodies (DSA) is widely accepted to be a risk factor for decreased graft survival after kidney transplantation. This entity also plays a pathogenic role in other solid organ transplants as it appears to be an increasingly common cause of heart graft dysfunction and an emerging issue in lung transplantation. In contrast, the liver appears relatively resistant to DSA-mediated injury. This "immune-tolerance" liver property has been sustained by a low rate of liver graft loss in patients with preformed DSA and by the intrinsic liver characteristics that favor the absorption and elimination of DSA; however, alloantibody-mediated adverse consequences are increasingly being recognized, and several cases of acute AMR after ABO-compatible liver transplant (LT) have been reported. Furthermore, the availability of new solid-phase assays, allowing the detection of low titers of DSA and the refinement of objective diagnostic criteria for AMR in solid organ transplants and particularly in LT, have improved the recognition and management of this entity. A cost-effective strategy of DSA monitoring, avoidance of class II human leukocyte antigen mismatching, judicious immunosuppression attached to a higher level of clinical suspicion of AMR, particularly in cases unresponsive to conventional anti-rejection therapy, can allow a rational approach to this threat.

Antibody-mediated rejection in liver transplantation: Current controversies and future directions

Interest in the role of donor-specific human leukocyte antibodies in liver transplantation has been rekindled recently. Emerging evidence suggests that these antibodies may cause injury to the liver allograft. Here we review the clinical literature, highlight controversial results, and propose a path forward for the definition and better understanding of antibody-mediated injury to the liver.

The Role of Donor Specific Antibodies in Liver Transplantation and Impact on Graft Survival on Positive Crossmatchs

Introduction: The role of donor specific antibodies in liver transplantation is unclear. Though donor-specific alloantibodies (DSA) has been shown to no immediate impact via hyperacute rejection, the long term impact on graft survival is not well elucidated. Methods: We followed 42 liver transplants (LT) patients with positive DSA since 1989. The HLA specificities of the antibodies were characterized using a Luminex-based, CDC DSA and CDC PRA. Flow cytometry was also obtained in 32 of the 42 patients. Graft survival was measured at 1, 3, 5 and 10 years and compared to a control group from our institution with negative cross match. A liver biopsy was performed when Acute Cellular Rejection (ACR) was suspected Results: A retrospective analysis shows that 76% of the grafts survived after 1 year. 71%, 54% and 37% graft survival was seen in 3, 5 and 10 years. The degree of PRA/DSA did not influence in terms of the long term survival of the graft. (Table 1)[Table 1. Graft survival comparison between positiv]Our control group showed a graft survival of 84%, 76%, 65% and 45% at 1, 3, 5 and 10 years follow up. ACR was biopsy positive in 8 of 11 patients with 100% of the rejection episodes before completing the first year after the transplant. Conclusion: Hyperacute rejection of a transplanted liver is rare even when the recipient has circulating donor-specific alloantibodies (DSA). Comparing to our control group, LT from positive DSA grafts has a decrease graft survival short and long term. ACR is common in the positive group especially during the first year after LT. Close attention during the first year of transplant is needed in order to prevent decrease in long term graft function on LT patients with positive crossmatch.

Prevalence, Course and Impact of HLA Donor-Specific Antibodies in Liver Transplantation in the First Year

The presence of preformed donor-specific HLA antibodies (DSA) in liver transplant recipients is increasingly recognized; however, the prevalence of DSA and their impact on early allograft function remains unknown. We prospectively followed serum DSA levels of 90 consecutive liver transplant recipients from baseline to 4 months. Twenty recipients (22.2%) had preformed DSA. No antibody-targeting treatments were undertaken. Seven days after transplantation, DSA levels decreased markedly in all but three patients. Day 7 protocol biopsies showed diffuse C4d deposition along the portal stroma, central vein, subendothelial and stromal space in the patients with persistent high DSA levels. The rate of acute cellular rejection was not significantly different in patients with DSA. The transaminase and bilirubin levels remained comparable during the first year despite the presence of DSA. The three patients with persistently high DSA levels continue to have normal allograft function. We conclude that in most cases, DSA disappear after liver transplant, however in rare instances where they persist, there is evidence of complement activation in the liver allograft, without significant clinical impact in the first year.

Evidence for no relevance of anti-major histocompatibility complex class i-related chain a antibodies in liver transplantation

The polymorphic major histocompatibility complex class I-related chain A (MICA) antigen is being increasingly recognized as a potential target molecule for immune cells during allograft rejection. Here we studied whether MICA is a target antigen for antibodies in liver transplant patients. Eighty-four patients were investigated for the presence of MICA antibodies before and after liver transplantation with MICA-transfected cells and flow cytometry. MICA typing was performed by polymerase chain reaction. Expression of MICA in liver cells was determined by reverse-transcription polymerase chain reaction, Western blotting, and flow cytometry. Liver biopsy specimens from liver transplant patients were examined for MICA expression. A total of 22 of 84 (26%) patients had MICA antibodies either pre-transplant (8/84, 9.5%) or post-transplant (14/84, 17%). No correlation between rejection frequencies (14/22, 63%) or other clinical parameters was observed in patients with MICA antibody versus those without MICA antibody (29/62, 47% P = not significant). We found weak messenger RNA expression for MICA in liver cells but no protein or cell surface expression. In addition, no MICA expression in liver biopsy sections from liver transplant patients was observed at any time point, including rejections. Thus, our preliminary results demonstrate no causal relationship between the presence of MICA antibodies and liver allograft rejections. Therefore, it is likely that MICA may not be an important target antigen during liver allograft rejections.

Neutralization of hepatitis B virus (HBV) by human monoclonal antibody against HBV surface antigen (HBsAg) in chimpanzees

The virus neutralizing efficacy of HB-C7A, a human monoclonal antibody raised against the surface antigen of hepatitis B virus (HBsAg), was proved using hepatitis B virus (HBV)-naïve chimpanzees. One control chimpanzee which received 100 CID 50 of HBV, subtype adw, without HB-C7A antibody became infected by HBV as evidenced by the appearance of HBV DNA on week 10 and subsequent appearance of HBsAg, anti-HBc and anti-HBs in the serum. Two experimental chimpanzees were inoculated intravenously with same dose of HBV as the control chimpanzee, which was previously incubated with 0.1 mg and 10 mg of HB-C7A antibody prior to inoculation. HBV infection was not observed in the antibody-treated chimpanzees during 12 months of follow-up, exhibiting neither detectable HBsAg nor anti-HBc antibody. This work demonstrates the neutralization of HBV by HB-C7A monoclonal antibody and shows the possibility of prevention of HBV infection using this antibody in liver transplantation and exposure to HBV.

Preformed antibodies detected by cytotoxic assay or multibead array decrease liver allograft survival: Role of human leukocyte antigen compatibility

The significance of human leukocyte antigen (HLA) compatibility and preformed antibodies in liver transplantation remains unclear. The objectives of this study were to evaluate, in a single-center cohort comprising 896 liver transplants, whether the degree of donor-recipient compatibility and preformed antibodies modified graft survival. Univariate Kaplan-Meier analysis demonstrated that donor-recipient HLA compatibility had a marginal impact on allograft survival. As for compatibility at individual antigen loci, 2 mismatches at HLA-A conferred a survival advantage in retransplanted allografts (P = 0.011). HLA-B and HLA-DR loci did not play a significant role in outcome in any pathology. The concordance of results on preformed antibodies detected by complement-dependent cytotoxicity (CDC) and a multiple bead assay (Luminex xMAP) showed a strong correlation between both techniques (P < 0.0001). Both CDC-detected and Luminex-detected antibodies were associated with shorter graft survival within the first year post-transplant (P = 0.01 and P = 0.016, respectively). Positive CDC T crossmatches and Luminex-detected HLA class II antibodies played a significant role in decreasing graft survival (P = 0.043 and P = 0.0019 at 1 year, respectively, and P = 0.005 and P = 0.038 at 5 years, respectively). A correlation was also observed between the presence of preformed Luminex-detected class II or Luminex I and II antibodies and allograft rejection (P = 0.001 and P = 0.042, respectively). In conclusion, although HLA typing is not a prerequisite for transplantation, screening of HLA antibodies with Luminex techniques and CDC crossmatch may be useful in the detection of at-risk patients that could benefit from increased surveillance and tailored therapy following transplantation.

Experimental and Clinical Significance of Antinuclear Antibodies in Liver Transplantation

Histone H1 and high-mobility group box 1 (HMGB1) proteins are known to initiate an immune reaction, and the corresponding antibodies (Abs) possess immunosuppressive activity. In the present study, we aimed to evaluate the immunological role of antinuclear Abs in experimental and clinical liver transplantation. In a rat tolerogenic orthotopic liver transplantation (OLT) model, antihistone H1 and HMGB1 titers were induced during the rejection and tolerance induction phases, respectively. Those Ab responses also were confirmed in a drug-induced tolerance model (acute rejection model + cyclosporin A [0 to 14 days after OLT]). We also found a similar tendency in our clinical drug-free patient (who experienced complete cessation of any immunosuppressive treatments) and that antinuclear Abs induced in the serum after cessation of immunosuppressants play a part of immune privilege in this patient. These results suggest that antinuclear Abs are important factors for overcoming rejection and the subsequent tolerance induction in liver transplantation.

Equal overall rejection rate in pre-transplant flow-cytometric cross-match negative and positive adult recipients in liver transplantation

T cell IgG flow-cytometric cross-matches (FCXM) using 48 stored pre-transplant patient serum samples and 40 stored serum samples collected 3 wk after liver transplantation and frozen spleen cells of cadaveric donors in 48 consecutive liver transplantations were performed retrospectively. T cell IgG FCXM using pre-transplant serum samples was compared with 46 complement-dependent lymphocytotoxic cross-matches (CDCXM) performed at the time of transplantation. Clinical relevance of these tests was evaluated in relation to acute rejection, 1-, 3- and 5-yr graft and patient survival. The incidence of positive FCXM was 33% (16 of 48) and 13% (six of 46) by CDCXM. The median time of acute rejection was 29 d after transplantation in FCXM positive group (range 13-101 d) and 22 d in FCXM negative group (range 7-157 d, NS). Rejection rate was similar in 16 pre-transplant FCXM positive patients (eight of 16, 50%) compared with six pre-transplant CDCXM positive patients (three of six, 50%; NS). Recipients having graft rejection tended to be more often pre-transplant FCXM positive (eight of 21, 38%) than CDCXM positive (three of 21, 14%), but the difference was not significant (p > 0.1). No difference was found in the positive predictive value in relation to acute rejection between positive FCXM and CDCXM (69% vs. 50%; NS). Furthermore there was no correlation between post-transplant positive FCXM and acute rejection. No difference was found between pre-transplant T cell IgG FCXM positive and negative recipients in relation to graft or patient survival. Our findings are supportive for little risk associated with preformed donor-specific antibodies in liver transplantation.

Immunosuppression with calcineurin inhibitors and polyclonal antibodies in liver transplantation

Immunosuppression with calcineurin inhibitors and polyclonal antibodies in liver transplantation

P732 - IgA anti-donor antibodies in liver transplantation

P732 - IgA anti-donor antibodies in liver transplantation