Imaging of T cell-mediated inflammation in a preclinical GvHD model using radiolabeled anti-human CD3 antibody

Ziel/Aim:

Hematopoietic stem cell transplantation is the only curative treatment for several hematological malignancies and immune deficiency syndromes. Nevertheless, the development of a graft-versus-host-disease (GvHD) after transplantation is a severe complication with high morbidity and mortality. The aim of this study was to image human inflammatory T cells during the development of GvHD and their migration into GvHD-related organs. By using a radiolabeled anti-human CD3 monoclonal antibody (mAb) we were able to visualize the progression of the disease in a humanized mouse model.

Methodik/Methods:

Transfer of human peripheral blood mononuclear cells (PBMC) into immunodeficient mice results in severe GvHD, mainly triggered by human CD4⁺ T cells. Some mice also received regulatory T cells (Treg) together with PBMC. T cell migration was visualized by sequential small animal PET/MRI using Zr-89-labeled anti-human CD3 mAb. Flow cytometry and immunohistochemistry was used to measure T cell frequencies in relevant organs at different time-points after engraftment.

Ergebnisse/Results:

Using radiolabeled anti-CD3 mAb, we successfully visualized human T cells in inflamed organs of mice by Zr-89-CD3-PET/MRI. Upon GvHD progression we observed increased numbers of human T cells in liver and spleen which correlated with clinical symptoms (GPT levels, weight loss). In vivo findings were confirmed by flow cytometry and immunohistochemical analysis. The liver showed distinct spot-like lesions in GvHD mice representing strong accumulation of T cells. Administration of Treg prior GvHD induction reduced the expansion of inflammatory T cells and concomitantly prevented GvHD in those mice.

Schlussfolgerungen/Conclusions:

Here we used radiolabeled anti-human CD3 mAb as a proof-of-concept to detect the exact spatio-temporal distribution of GvHD-mediating T cells. In the future, radiolabeled T cell-specific mAb could be used as a predictive early biomarker during the course of GvHD maybe even before clinical signs of the disease become evident.