Cytomegalovirus-Associated Inhibition of Hematopoiesis Is Preventable by Cytoimmunotherapy With Antiviral CD8 T Cells.

Angelique Renzaho,Jürgen Podlech,Niels A W Lemmermann,Franziska Blaum,Matthias J Reddehase,Birgit Kühnapfel

doi:10.3389/fcimb.2020.00138

Abstract

Reactivation of latent cytomegalovirus (CMV) in recipients of hematopoietic cell transplantation (HCT) not only results in severe organ manifestations, but can also cause “graft failure” resulting in bone marrow (BM) aplasia. This inhibition of hematopoietic stem and progenitor cell engraftment is a manifestation of CMV infection that is long known in clinical hematology as “myelosuppression.” Previous studies in a murine model of sex-chromosome mismatched but otherwise syngeneic HCT and infection with murine CMV have shown that transplanted hematopoietic cells (HC) initially home to the BM stroma of recipients but then fail to further divide and differentiate. Data from this model were in line with the hypothesis that infection of stromal cells, which constitute “hematopoietic niches” where hematopoiesis takes place, causes a local deficiency in essential hematopoietins. Based on this understanding, one must postulate that preventing infection of stromal cells should restore the stroma's capacity to support hematopoiesis. Adoptively-transferred antiviral CD8+ T cells prevent lethal CMV disease by controlling viral spread and histopathology in vital organs, such as liver and lungs. It remained to be tested, however, if they can also prevent infection of the BM stroma and thus allow for successful HC engraftment. Here we demonstrate that antiviral CD8+ T cells control stromal infection. By tracking male donor-derived sry+ HC in the BM of infected female sry− recipients, we show the CD8+ T cells allow for successful donor HC engraftment and thereby prevent CMV-associated BM aplasia. These data provide a further argument for cytoimmunotherapy of CMV infection after HCT.

Highlights

The risk of cytomegalovirus (CMV) reactivation and consequent CMV disease remains a severe infectious complication in the treatment of hematopoietic malignancies by hematopoietic cell transplantation (HCT), which is the last therapeutic resort for aggressive leukemias that resist standard therapies
In accordance with cell culture data for the majority of tested human CMV clinical isolates (Apperley et al, 1989; Simmons et al, 1990), work in a cell culture model of murine myelopoiesis suggested that the cause of myelosuppression by murine cytomegalovirus (mCMV) is an infection of bone marrow (BM) stromal cells rather than of hematopoietic cells (HC) (Busch et al, 1991)
The mouse model of mCMV infection at the time of HCT was designed to mimic clinical cases of peri-transplantation reactivation of latent human CMV, with CMV disease/pneumonia becoming evident from 3 weeks postHCT onward

Summary

INTRODUCTION

The risk of cytomegalovirus (CMV) reactivation and consequent CMV disease remains a severe infectious complication in the treatment of hematopoietic malignancies by hematopoietic cell transplantation (HCT), which is the last therapeutic resort for aggressive leukemias that resist standard therapies. In accordance with cell culture data for the majority of tested human CMV clinical isolates (Apperley et al, 1989; Simmons et al, 1990), work in a cell culture model of murine myelopoiesis suggested that the cause of myelosuppression by mCMV is an infection of BM stromal cells rather than of HC (Busch et al, 1991) For testing this in vivo in a relevant clinical correlate, a sex-mismatched mouse model of HCT was established with HC from male donors, which carry the Y-chromosomal male-sex-determining gene sry (Gubbay et al, 1990; Koopman et al, 1990), and female sry− recipients, or vice versa, so that either donor HC or recipient’s BM stromal cells carry the sry gene as a reporter for donor or recipient origin (Mayer et al, 1997; Steffens et al, 1998b; Seckert et al, 2008, 2009).

MATERIALS AND METHODS

RESULTS AND DISCUSSION

DATA AVAILABILITY STATEMENT