Long-term lung transplantation in nonhuman primates

Abstract

Despite advances in surgical technique and clinical care, lung transplantation still remains a short-term solution for the treatment of end-stage lung disease. To date, there has been limited experience in experimental lung transplantation using nonhuman primate models. Therefore, we have endeavored to develop a long-term, nonhuman primate model of orthotopic lung transplantation for the ultimate purpose of designing protocols to induce tolerance of lung grafts. Here, we report our initial results in developing this model and our observation that the nonhuman primate lung is particularly prone to rejection. This propensity toward rejection may be a consequence of 1) upregulated nonspecific inflammation, and 2) a larger number of pre-existing alloreactive memory T cells, leading to augmented deleterious immune responses. Our data show that triple-drug immunosuppression mimicking clinical practice is not sufficient to prevent acute rejection in nonhuman primate lung transplantation. The addition of horse-derived anti-thymocyte globulin and a monoclonal antibody to the IL-6 receptor allowed six out of six lung recipients to be free of rejection for over 120 days.

Keywords: Immunosuppressant; animal models: nonhuman primate; basic (laboratory) research/science; fusion proteins and monoclonal antibodies; immunosuppressant; lung transplantation/pulmonology; polyclonal preparations.

Figure 1

Lung histology showing no evidence for rejection in an autotransplanted lung (#M4809, Day 35, H&E 50X).

Figure 2

Lung histology showing high-grade rejection of an MHC-mismatched lung in a nonimmunosuppressed recipient (#M3805, Day 5, Verhoeff’s stain 50X).

Figure 3

Lung histology showing healthy graft (#M4012 [Group 2], Day 96, H&E 50X).

Figure 4

Lung histology showing healthy graft (#M4209 [Group 3], Day 97, H&E 50X).

Figure 5

hATG+anti-IL6RmAb (n=3) have asynergistic effect on the expansion of circulating regulatory T cells, compared to either hATG (n=1) or anti-IL6R mAb (n=1) alone.

Figure 6

Transient increase in CD25⁺Foxp3⁺ T lymphocytes after treatment with hATG and anti-ILSR mAb (#M1407).