Prevalence and Clinical Impact of Donor-Specific Alloantibody Among Intestinal Transplant Recipients

Cheng, Elaine; Everly, Matthew J; Kaneku, Hugo; Banuelos, Nubia; Wozniak, Laura J.; Venick, Robert S.; Marcus, Elizabeth A.; McDiarmid, Suzanne V.; Busuttil, Ronald W.; Terasaki, Paul I.; Farmer, Douglas G.

doi:10.1097/tp.0000000000001391

Cited by 63 publications

(72 citation statements)

References 44 publications

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“…Multiple studies over recent years have provided strong evidence in support of the association between the development of donor HLA-specific alloantibodies and the risk of acute antibodymediated rejection, chronic rejection and allograft loss across all solid organ transplants (42,(49)(50)(51)(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

Predicting humoral alloimmunity from differences in donor-recipient HLA surface electrostatic potential

Mallon

Kling

Robb

et al. 2018

Preprint

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In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure but our ability to assess the immunological risk associated with a potential donor-recipient HLA combination is limited. We hypothesised that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared to recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level (electrostatic mismatch score-three dimensional; EMS-3D). We then examined humoral alloimmune responses in healthy females subjected to a standardised injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Discussionmentioning

confidence: 99%

Predicting humoral alloimmunity from differences in donor-recipient HLA surface electrostatic potential

Mallon

Kling

Robb

et al. 2018

Preprint

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“…11,12 Briefly, from 1991 to 1995, patients were treated with OKT3 or rabbit antithymocyte globulin (ATG) induction. 11,12 Briefly, from 1991 to 1995, patients were treated with OKT3 or rabbit antithymocyte globulin (ATG) induction.…”

Section: Management Protocolsmentioning

confidence: 99%

“…Over this nearly 25-year experience, management protocols have evolved and have been described in detail elsewhere. 11,12 Briefly, from 1991 to 1995, patients were treated with OKT3 or rabbit antithymocyte globulin (ATG) induction. From 1996 to 1999, no induction antibody was used and patients were treated with IV cyclophosphamide or mycophenolate mofetil (MMF) in the early post-ITx period.…”

Section: Management Protocolsmentioning

confidence: 99%

Clinical characteristics and outcomes of PTLD following intestinal transplantation

Wozniak

Mauer

Venick

et al. 2018

Clinical Transplantation

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Post-transplant lymphoproliferative disease (PTLD) has the highest incidence following intestinal transplantation (ITx). Our center has seen a recent increase in PTLD. Our aim was to review a single-center PTLD experience with a focus on clinical characteristics and outcomes. We completed a retrospective review of biopsy-proven PTLD cases using a prospectively maintained database of 115 ITx recipients transplanted between 1991 and 2014. Nineteen (17%) ITx recipients developed 25 PTLD cases during a median follow-up time of 6.4 (1.6-14.6) years. The incidence of early PTLD was 6% (n = 7). There was a trend toward increased risk of PTLD in children compared with adults (P = .11) and a significantly increased risk of PTLD in re-ITx compared with primary ITx recipients (P = .03). Most PTLD cases were diagnosed between 2010 and 2014 (n = 14). All early PTLD cases were EBV+ on in situ hybridization. Overall graft and patient survival are 68% and 74%, respectively. Second episodes of PTLD were diagnosed in 43% of surviving pediatric patients. Our program has a low incidence of early PTLD with overall excellent graft and patient survival following diagnosis. However, we have also seen a rising incidence of late PTLD. The cause of the increase is unknown as no major changes in immunosuppression protocols have occurred since 1999.

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“…There is still no consensus on the diagnostic criteria for humoral rejection, and although there is growing evidence of the negative impact of donor‐specific antibodies (DSA), intestinal rejection continues to be managed with immunosuppressive therapies focused on the cellular mechanisms of the immune response. In recent years some studies have reported the impact of DSA in intestinal graft outcome, but the experience is still limited and some results are controversial. The relationship between the presence of DSA and an increased incidence of rejection and allograft loss is well recognized in solid organ transplantation, and progress has been made in defining which antibodies are really deleterious, demonstrating worse prognosis with complement‐fixing DSA in kidney, liver, heart, and lung transplantation .…”

mentioning

confidence: 99%

“…The liver inclusion in multivisceral and hepatointestinal transplants has been described to have a beneficial effect on allograft outcome, although some authors reported better results in isolated intestinal grafts . Histocompatibility mismatching has also been associated with the emergence of de novo donor‐specific antibodies (dnDSA) in some studies, but again the results are controversial …”

mentioning

confidence: 99%

Donor‐Specific Antibodies in Pediatric Intestinal and Multivisceral Transplantation: The Role of Liver and Human Leukocyte Antigen Mismatching

et al. 2018

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Rejection is one of the most important drawbacks for graft and patient survival in intestinal and multivisceral transplantation. However, there is no consensus on the diagnostic criteria for humoral rejection, and the literature about the role of donor-specific antibodies (DSA) on allograft outcome and the risk factors that contribute to their development is scant with contradictory results. The present study analyzes the role of DSA exclusively in a pediatric cohort of 43 transplants. Among our patients, 11.6% showed preformed DSA, but they did not correlate with more rejection or less allograft survival. Having previous transplants was the main sensitization factor with an odds ratio (OR) = 44.85 (P = 0.001). In total, 16.3% of recipients developed de novo donor-specific antibodies (dnDSA), mostly directed against human leukocyte antigen (HLA) class II, polyspecific and complement fixing. Additionally, the presence of dnDSA had a deleterious effect on graft rejection (hazard ratio [HR] = 11.00; P = 0.01) and survival (HR = 66.52; P < 0.001) in an observational period of 5 years after transplantation. The inclusion of the liver emerged as the main protective factor against dnDSA development with an OR = 0.07 (P = 0.007). The analysis of HLA compatibility at the serological and epitope level with the computational tools HLAMatchmaker and PIRCHE revealed no association between HLA mismatching and dnDSA. In conclusion, this study performed in pediatric recipients shows the deleterious effect of dnDSA on intestinal transplantation supported by the complement-fixing activity observed. Additionally, the liver inclusion in the allografts showed to be a protective factor against dnDSA generation.

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Prevalence and Clinical Impact of Donor-Specific Alloantibody Among Intestinal Transplant Recipients

Cited by 63 publications

References 44 publications

Predicting humoral alloimmunity from differences in donor-recipient HLA surface electrostatic potential

Predicting humoral alloimmunity from differences in donor-recipient HLA surface electrostatic potential

Clinical characteristics and outcomes of PTLD following intestinal transplantation

Donor‐Specific Antibodies in Pediatric Intestinal and Multivisceral Transplantation: The Role of Liver and Human Leukocyte Antigen Mismatching

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