Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction

Iasella, Carlo J.; Ensor, Christopher R.; Marrari, Marilyn; Mangiola, Massimo; Xu, Qingyong; Nolley, Eric P.; Moore, Cody A.; Morrell, Matthew R.; Pilewski, Joseph M.; Sánchez, Pablo G.; McDyer, John F.; Zeevi, Adriana

doi:10.1016/j.healun.2020.09.003

Cited by 26 publications

(26 citation statements)

References 33 publications

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“…We observed a significant reduction in total DSA among recipients of induction that was driven by significantly lower DSA in patients with a combination of Class I and Class II and those with Class II DSA only. The mitigation of DSA in these categories is critical because the presence of de novo class II or both Class I + II DSA, especially DQ‐specific DSA, is associated with increased AMR and CLAD 25,27–30 . The ability to ameliorate these particular DSA adds further intrigue and promise to the potential benefits of the abbreviated rATG induction regimen in LTR.…”

Section: Discussionmentioning

confidence: 99%

Antithymocyte globulin is associated with a lower incidence of de novo donor‐specific antibody detection in lung transplant recipients: A single‐center experience

Narula

Khouzam

Álvarez

et al. 2021

Immunity Inflam & Disease

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Purpose Induction immunosuppression has improved the long‐term outcomes after lung transplant. This is the first report exploring the association of induction immunosuppression with the development of de novo donor‐specific human leukocyte antigen (HLA) antibodies (DSA) in lung transplant recipients (LTR). Methods Sixty‐seven consecutive primary LTR were followed for 3 years posttransplant. A total of 41/67 (61%) LTR‐received induction immunosuppression using a single dose of rabbit Antithymocyte Globulin (rATG; 1.5 mg/kg) within 24 h of transplant. All recipients had a negative flow cytometry crossmatch on the day of transplant. Serum samples at 1, 3, 6, and 12 months posttransplant were assessed for the presence of de novo HLA DSA. Results De novo HLA DSA were detected in 22/67 (32.8%) LTR within 1‐year posttransplant. Of these, 9/41 (21.9%) occurred in the induction therapy group and 13/26 (50%) in the noninduction group. Class II DSA were detected in 3/41 (7.3%) LTR who received induction compared to 9/26 (34.6%) LTR without induction immunosuppression (p = .005). Differences in overall survival or freedom from chronic lung allograft dysfunction rates between the two groups were not statistically significant. Conclusion Induction immunosuppression utilizing a modified regimen of single‐dose rATG is associated with a significant reduction in de novo DSA production in LTR.

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Section: Discussionmentioning

confidence: 99%

Antithymocyte globulin is associated with a lower incidence of de novo donor‐specific antibody detection in lung transplant recipients: A single‐center experience

Narula

Khouzam

Álvarez

et al. 2021

Immunity Inflam & Disease

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“…These findings are raising the possibility that RAS might have common characteristics with chronic AMR. A recent trial showed that DSA persistence, C1q binding, and DQ specificity are independent risk factors for increased risk of CLAD and worse outcomes in lung transplant recipients 22 …”

Section: Pathogenesismentioning

confidence: 99%

Restrictive allograft syndrome after lung transplantation

Klouda

Vargas

Midyat

2021

Pediatric Transplantation

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More than 60,000 lung transplants have been performed at centers around the world to date. Although there has been some improvement, especially in early survival, long-term outcomes have changed little over the years and are primarily limited by the development of chronic lung allograft dysfunction (CLAD). 1 CLAD is predominantly a consequence of chronic rejection and can present in different phenotypes which are characterized by airway obstruction, restriction, or a mixed type. The pathogenesis is unknown, and hypoxia, autoimmunity, recurrent inflammation, infection, and damage to lung structure upon harvest have all been hypothesized to trigger the development of CLAD. 2 Because of the important physiologic differences between these phenotypes, different diagnostic and therapeutic approaches might be warranted for each.In 1993, Cooper et al introduced the first definition of "bronchiolitis obliterans syndrome" (BOS) which is the key manifestation and the most common form of CLAD. 3 BOS represents the obstructive form of CLAD, and it is thought to be the pathologic hallmark of chronic rejection and the clinical correlate of bronchiolitis obliterans (BO). BOS is a clinical syndrome, and its diagnosis is mostly based on the presence of obstructive spirometry findings when other disease processes have been excluded, such as infection. 4

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“…6 Relevant to this study, in adults the development of antibodies directed at donor Human Leukocyte Antigen (HLA) molecules strongly associates with the development of CLAD. [7][8][9][10][11][12][13][14] Importantly, while retransplantation for CLAD is feasible, it has limited practical utility due to organ scarcity and reduced survival after a second transplant for any indication. [15][16][17] Thus, the identification of therapies capable of preventing CLAD and improving outcomes in pediatric LTRs represents a crucial unmet medical need.…”

Section: Introductionmentioning

confidence: 99%

CTOTC-08: A multicenter randomized controlled trial of rituximab induction to reduce antibody development and improve outcomes in pediatric lung transplant recipients

Sweet

Blatter

Chin

et al. 2022

American Journal of Transplantation

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We conducted a randomized, placebo‐controlled, double‐blind study of pediatric lung transplant recipients, hypothesizing that rituximab plus rabbit anti‐thymocyte globulin induction would reduce de novo donor‐specific human leukocyte antigen antibodies (DSA) development and improve outcomes. We serially obtained clinical data, blood, and respiratory samples for at least one year posttransplant. We analyzed peripheral blood lymphocytes by flow cytometry, serum for antibody development, and respiratory samples for viral infections using multiplex PCR. Of 45 subjects enrolled, 34 were transplanted and 27 randomized to rituximab (n = 15) or placebo (n = 12). No rituximab‐treated subjects versus five placebo‐treated subjects developed de novo DSA with mean fluorescence intensity >2000. There was no difference between treatment groups in time to the primary composite outcome endpoint (death, bronchiolitis obliterans syndrome [BOS] grade 0‐p, obliterative bronchiolitis or listing for retransplant). A post‐hoc analysis substituting more stringent chronic lung allograft dysfunction criteria for BOS 0‐p showed no difference in outcome (p = .118). The incidence of adverse events including infection and rejection episodes was no different between treatment groups. Although the study was underpowered, we conclude that rituximab induction may have prevented early DSA development in pediatric lung transplant recipients without adverse effects and may improve outcomes (Clinical Trials: NCT02266888).

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Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction

Cited by 26 publications

References 33 publications

Antithymocyte globulin is associated with a lower incidence of de novo donor‐specific antibody detection in lung transplant recipients: A single‐center experience

Antithymocyte globulin is associated with a lower incidence of de novo donor‐specific antibody detection in lung transplant recipients: A single‐center experience

Restrictive allograft syndrome after lung transplantation

CTOTC-08: A multicenter randomized controlled trial of rituximab induction to reduce antibody development and improve outcomes in pediatric lung transplant recipients

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