Noninvasive Imaging of Human Immune Responses in a Human Xenograft Model of Graft-Versus-Host Disease

Abstract

The immune system plays a crucial role in many diseases. Activation or suppression of immunity is often related to clinical outcome. Methods to explore the dynamics of immune responses are important to elucidate their role in conditions characterized by inflammation, such as infectious disease, cancer, or autoimmunity. Immuno-PET is a noninvasive method by which disease and immune cell infiltration can be explored simultaneously. Using radiolabeled antibodies or fragments derived from them, it is possible to image disease-specific antigens and immune cell subsets. Methods: We developed a method to noninvasively image human immune responses in a relevant humanized mouse model. We generated a camelid-derived single-domain antibody specific for human class II major histocompatibility complex products and used it to noninvasively image human immune cell reconstitution in nonobese diabetic severe combined immune deficiency g2/2 mice reconstituted with human fetal thymus, liver, and liver-derived hematopoietic stem cells (BLT mice). Results: We showed imaging of infiltrating immunocytes in BLT mice that spontaneously developed a graft-versus-host-like condition, characterized by alopecia and blepharitis. In diseased animals, we showed an increased PET signal in the liver, attributable to infiltration of activated class II major histocompatibility complex 1 T cells. Conclusion: Noninvasive imaging of immune infiltration and activation could thus be of importance for diagnosis and evaluation of treatment of graft-versus-host disease and holds promise for other diseases characterized by inflammation.

Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells

“…1 A ; Saerens and Muyldermans, 2012 ). These fragments are ∼15 kD in size and readily lend themselves to sortase-catalyzed enzymatic modifications for a variety of purposes, including the installation of radioisotopes for PET imaging ( Rashidian et al, 2015a , b ; Van Elssen et al, 2017 ).…”

18F-3′-Deoxy-3′-Fluorothymidine Positron Emission Tomography Imaging for the Prediction of Acute Graft-Versus-Host Disease in Mouse Hematopoietic Stem Cell Transplant Models

“…In other work by Van Elssen et al [21], the authors utilized radiolabeled antibody fragments Variable Fragments of Heavy Chain Antibodies (VHH) to target human Class II MHC molecules expressed on a variety of immune cells. Using a humaninto-mouse xenograft system, the authors focused on the imaging of GVHD target organs after the development of overt clinical disease.…”

Nanobodies as non-invasive imaging tools

“…To image human immune responses, an anti-human class II MHC nanobody was developed. 53 The radiolabeled nanobody was used in a relevant humanized mouse model: NOD-SCID mice reconstituted with human fetal thymus, liver and liver-derived hematopoietic stem cells (BLT mice). These animals spontaneously develop graft-versus-host disease, characterized by alopecia and blepharitis.…”