T-Cell Depletion Versus Interleukin-2 Antagonists in a Kidney Transplant Model of Sensitized Rhesus Macaques
1Emory University, Atlanta, GA
2Medical University Vienna, Vienna, Austria
3Duke University, Durham, NC.
Meeting: 2015 American Transplant Congress
Abstract number: C13
Keywords: Antibodies, Induction therapy, Primates, Sensitization
Session Information
Session Name: Poster Session C: Antigen Presenting Cells in Alloimmune Responses/B Cells and Antibody in Alloimmune Responses
Session Type: Poster Session
Date: Monday, May 4, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
[Background] Sensitized patients comprise up to a third of the kidney waiting list. Preformed and newly formed alloantibodies post transplantation (TX) deteriorate graft survival, recall responses in T cells add damage. Induction with Interleukin-2 (IL-2) antagonists has been used as alternative to depleting antibodies in humans after desensitization. We tested both induction regimens in a rigorous model of kidney TX in sensitized non-human primates (NHP).
[Methods] Fully mismatched rhesus macaques were sensitized with skin TX. Immunologic responses were monitored by T- and B-cell flow crossmatches. After stabilization the animals underwent native nephrectomy and kidney TX from their prior skin donor. In one group (n=4, BAS) immunosuppression (IS) included induction with Basiliximab and maintenance therapy using Tacrolimus and Mycophenolate and tapered methylprednisolone. In the second group (n=7, DEPL) we induced with T-cell depletion using anti-rhesus CD4 and CD8 antibodies. Assessment comprised laboratory testing, flow cytometry of lymphocytes and DSA, urine output and clinical monitoring. After sacrifice kidney grafts were submitted to pathology for H&E, PAS and C4d staining.
[Results] T-cell depletion was effective, reducing mean CD4 cells by 93.5% and CD8 cells by 100% (p=0.0042) in the first week after TX; this was sustained until the end point. All sensitized animals had to be sacrificed due to worsening clinical state and concomitant kidney failure. One monkey in the DEPL-group suffered hyperacute rejection. The remaining DEPL-animals survived longer (mean survival time 22+/-18.6 days) than in the BAS- group (3.75+/-3.1 days; p=0.0432). Histology revealed cellular rejection in 66% of rejected BAS grafts, in the DEPL-group isolated humoral rejection was found in 83% of rejected grafts, one DEPL-animal with mixed rejection was retrospectively found to have had suboptimal T-cell depletion.
[Conclusion] These results show that kidney TX into sensitized recipients using IL-2 antagonist subjects grafts to predominant T-cell damage. In T-cell depleted animals humoral mechanisms stir graft rejection. We think that latter group mimics well clinical humoral rejection in sensitized human patients and can therefore be used as model for testing experimental desensitization strategies in the future.
To cite this abstract in AMA style:
Burghuber C, Kwun J, Page E, Leopardi F, Gibby A, Farris A, Iwakoshi N, Knechtle S. T-Cell Depletion Versus Interleukin-2 Antagonists in a Kidney Transplant Model of Sensitized Rhesus Macaques [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/t-cell-depletion-versus-interleukin-2-antagonists-in-a-kidney-transplant-model-of-sensitized-rhesus-macaques/. Accessed October 15, 2024.« Back to 2015 American Transplant Congress