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T and B Lymphocyte Dynamics after Genetically-Modified Pig-To-Baboon Kidney Xenotransplantation with an Anti-CD40mAb-Based Immunosuppressive Regimen

A. Jagdale1, H. Iwase1, H. Nguyen1, T. Yamamoto1, D. Ayares2, D. Anderson1, D. Eckhoff1, D. Cooper1, H. Hara1

1Surgery, University of Alabama at birmingham, Birmingham, AL, 2Revivicor, Blacksburg, VA, VA

Meeting: 2020 American Transplant Congress

Abstract number: 101

Keywords: CD20, CD3, Kidney transplantation, Outcome

Session Information

Date: Saturday, May 30, 2020

Session Name: Xenotransplantation

Session Time: 3:15pm-4:45pm

 Presentation Time: 4:15pm-4:27pm

Location: Virtual

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*Purpose: We have evaluated recovery of T and B lymphocytes and their subsets after depletion by anti-thymocyte globulin (ATG) and an anti-CD20mAb (Rituximab), followed by genetically-engineered pig kidney Tx in baboons receiving an anti-CD40mAb-based maintenance immunosuppressive regimen.

*Methods: Life-supporting pig kidney Tx was performed (n=15). Induction therapy was with ATG (10mg/kg) on pre-Tx day-3, and anti-CD20mAb (10mg/kg) on day-2, aimed to achieve a CD3+T cell count of <500cells/mm2 and complete depletion of B lymphocytes in the blood. Maintenance therapy consisted of (i) anti-CD40mAb (50mg/kg), (ii) rapamycin (trough level 6-10ng/ml), and (iii) methylprednisolone (0.125mg/kg). Follow-up was for 6 months (n=4), or until graft loss from rejection (n=7), or discontinuation for other complications (n=4). Recipient baboon blood was collected pre-Tx (day-7) and at intervals post-Tx to measure (by flow cytometry) CD3+T, CD4+T, CD8+T, and CD22+B cell numbers. In addition, CD4+T and CD8+T cell subsets (naïve, central memory [CM], effector memory [EM]) and CD22+B cell subsets (naïve, non-switched memory, switched memory, double-negative) were measured.

*Results: After induction therapy, the total lymphocyte count fell by 85% within 2 weeks, and subsequently recovered to only approximately 20% of baseline level after 2 months (p<0.001). The absolute numbers of CD3+, CD4+, and CD8+T cells fell by >90% by day 0 (day of kidney Tx) (all p<0.001), and no CD22+B cells were measurable in the blood after day 7 (p<0.001). T cell numbers began to recover within 2 weeks, but only to <33% of the pre-ATG baseline number throughout 6 months’ follow-up (p<0.001 compared with baseline), even if rejection developed. Virtually no CD22+ B cells were measured in the blood until approximately 2 months after Tx (day 60), and recovery remained at <33% of the baseline (p<0.001). At 6 months, recovery of CD4+ naïve (<30%), CM (<40%), and EM (<10%) cells, and of CD8+ naïve (<20%), CM (<20%) cells was similar (all p<0.001 vs baseline), but CD8+ EM cells increased to 60% of baseline. Recovery at 6 months of CD22+ naïve (>60%), non-switched memory (10%), switched memory (<2%), and double-negative (<10%) cells indicated that a much greater percentage were naïve in contrast to baseline.

*Conclusions: ATG and anti-CD20mAb effectively decreased the numbers of T and B lymphocytes and, in the presence of anti-CD40mAb therapy, recovery of these cells remained at approximately 33% of baseline. Although the predominant subsets of CD4+T and CD22+B cells were naïve, the predominant subset of CD8+T cells was EM. Importantly, we could find no correlation between T or B or subset cell recovery and the development of rejection in the graft.

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To cite this abstract in AMA style:

Jagdale A, Iwase H, Nguyen H, Yamamoto T, Ayares D, Anderson D, Eckhoff D, Cooper D, Hara H. T and B Lymphocyte Dynamics after Genetically-Modified Pig-To-Baboon Kidney Xenotransplantation with an Anti-CD40mAb-Based Immunosuppressive Regimen [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/t-and-b-lymphocyte-dynamics-after-genetically-modified-pig-to-baboon-kidney-xenotransplantation-with-an-anti-cd40mab-based-immunosuppressive-regimen/. Accessed February 26, 2021.

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