Induction of persistent tolerance of lung transplants by IL-2 complex-stimulated regulatory T cells in vivo

Hintergrund:

Transplant (Tx) tolerance is a state of anergy by the recipient to Tx-related alloantigen. Lung allo-Tx has the worst allograft survival outcome when compared to all other transplantable solid organs. Interleukin (IL-) 2 promotes rejection through enhanced T cell-cytotoxicity. However, when binding IL-2 in complex (cplx) with a neutralizing anti-IL-2 antibody, it can induce expansion of regulatory T (Treg) cells. We therefore evaluated here the impact on allograft outcome of IL-2 cplx on experimental mouse lung Tx outcome.

Material und Methode:

Single lung Tx was performed from BALB/c to C57BL/6 mice to induce full allo-rejection. Recipients received intraperitoneal injections of either PBS (control) or IL-2cx with anti-IL-2 antibody clone JES6 – 1 on three consecutive days before Tx. The outcomes of transplants were analyzed on day 5, 15, 28 and 56 by flow cytometry, lung functionality (oxygenation and compliance) and histology.

Ergebnis:

Acute allo-Tx rejection (AR) was virtually absent macroscopically and histologically in IL-2cx-treated animals on day 5, 15, 28 and 56 compared to controls. AR scores of allo-transplants of IL-2cx-treated mice were significantly lower vs. control (day 5, p = 0.02; day 14, p < 0.001; day 28, p = 0.007; day 56, p = 0.04). Foxp3+CD4+CD25+ Treg cells in IL-2 cx-treated mice were significantly higher within allotransplants on all time point, while in contralateral naïve lungs and spleens on day 5 or 15 (p < 0.05). IL-2cx-treated allograft on day 5 had better compliance (5.2 ± 2.2 vs. 1.6 ± 0.8 µl/cmH2O, p = 0.04) and a better oxygenation (253 ± 136 vs. 24 ± 4 mmHg, p = 0.04) compared to the control.

Schlussfolgerung:

Treatment of recipients using IL-2cx before lung Tx leads to Treg expansion, prevents from AR and maintains a viable engrafted lung up to 56 days post lung Tx. These data provide insight into the mechanism of adaptive tolerance induction in Tx and may have implications for immune protocols for Treg modulation in human lung transplantation.