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Belatacept Augments Mixed Chimerism in a Novel Nonhuman Primate Kidney Transplant Tolerance Induction Protocol

S. C. Kim, C. J. Little, J. H. Fechner, P. J. Chlebeck, J. Post, A. D'Alessandro, D. B. Kaufman

University of Wisconsin, Madison, WI

Meeting: 2022 American Transplant Congress

Abstract number: 1281

Keywords: Co-stimulation, Mixed chimerism, Primates, Tolerance

Topic: Basic Science » Basic Science » 12 - Immunosuppression & Tolerance: Preclinical & Translational Studies

Session Information

Session Name: Immunosuppression & Tolerance: Preclinical & Translational Studies

Session Type: Poster Abstract

Date: Monday, June 6, 2022

Session Time: 7:00pm-8:00pm

 Presentation Time: 7:00pm-8:00pm

Location: Hynes Halls C & D

*Purpose: A novel protocol of antilymphocyte globulin (ATG), tomotherapy-based total lymphoid irradiation (TomoTLI), and adoptive cellular transfer was developed in a preclinical model of MHC-mismatched nonhuman primate (NHP) kidney transplantation. This study sought to provide insight into improved chimerism seen with the addition of costimulation blockade in this mixed chimerism-based tolerance induction model.

*Methods: ATG (4mg/kg x5 doses) with or without TomoTLI (12Gy over 10 fractions) and Belatacept (10mg/kg x4 doses) was applied to a 3-5 MHC antigen mismatched post-kidney transplant rhesus macaque model. Donor hematopoietic cells were infused after induction in the ATG+TomoTLI and ATG+TomoTLI+Bela cohorts. Maintenance immunosuppression consisted of mycophenolate mofetil (15mg/kg/day) and tacrolimus (trough 8-10ng/mL), which was tapered off by week 21 and 39, respectively. Allogeneic mixed lymphocyte reactions (MLRs) were utilized to assess in vitro alloreactivity.

*Results: ATG+TomoTLI (n=11) is more effective at immediate and sustained lymphocyte depletion at post conditioning days 7 (p=0.003), 14 (p<0.001), and 21 (p=0.006) compared to ATG induction therapy alone (n=2); however, there was a high rate of early (30 day) DSA production and resultant non-engraftment in 9 of 11 recipients. The addition of Belatacept (n=8) eliminated early DSA production, which yielded a higher frequency of transient mixed chimerism (18.1% vs 37.5%) (Figure 1). Furthermore this induction regimen consistently abated an early allo-MLR response 30-60 days after therapy irrespective of engraftment (p=0.008) (Figure 2), similar to operationally tolerant ATG+TomoTLI animals with a negative MLR response off all maintenance immunosuppression.

*Conclusions: The addition of Belatacept to ATG+TomoTLI maintains effective lymphocyte depletion while mitigating early DSA production, thus promoting allogeneic tolerance in a novel model of mixed chimerism-based operational tolerance in NHPs undergoing MHC-mismatched kidney transplantation.

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To cite this abstract in AMA style:

Kim SC, Little CJ, Fechner JH, Chlebeck PJ, Post J, D'Alessandro A, Kaufman DB. Belatacept Augments Mixed Chimerism in a Novel Nonhuman Primate Kidney Transplant Tolerance Induction Protocol [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/belatacept-augments-mixed-chimerism-in-a-novel-nonhuman-primate-kidney-transplant-tolerance-induction-protocol/. Accessed May 28, 2025.

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