Host and donor immune responses contribute to antiviral effects of amotosalen-treated donor lymphocytes following early posttransplant cytomegalovirus infection.

Abstract

We have previously shown that amotosalen-treated splenocytes rescued allorecipients from a lethal dose of mouse CMV (MCMV) administered on day 0 in experimental parent C57BL/6-->CB6F1 allogeneic bone marrow transplant. In this study, we investigated the mechanism of antiviral activity of amotosalen-treated donor splenocytes when sublethal MCMV infections were administered 7 days posttransplant. Recipients of 3 x 10(6) untreated splenocytes were used as control. Following MCMV infection, recipients of untreated splenocytes had 40% early mortality due to acute graft-vs-host disease compared with no deaths among recipients of 10 x 10(6) treated splenocytes. However, recipients of both types of donor splenocytes effectively cleared MCMV from their liver. Like the untreated CD8(+) T cells, amotosalen-treated CD8(+) T cells equally retained their in vivo CTL activity against MCMV early peptide-pulsed targets and expressed similar levels of granzyme B within 11 days of infection. In contrast to full donor chimerism in recipients of untreated splenocytes, recipients of amotosalen-treated splenocytes showed mixed chimerism with both donor spleen- and host-derived anti-MCMV CD8(+) T cells in their blood and lymphoid organs, with significantly higher numbers of host-derived CD4(-)CD8(-) (double negative) T cells in the spleens of recipients of treated splenocytes compared with the recipients of untreated splenocytes. Additionally, recipients of amotosalen-treated splenocytes had lower levels of serum IFN-gamma and TNF-alpha in response to MCMV infection compared with untreated recipients. Thus, adoptive immunotherapy with treated T cells is a novel therapeutic approach that facilitates hematopoietic engraftment and permits antiviral immunity of both donor and host T cells without graft-vs-host disease.

• Authors: Mohammad S Hossain, John D Roback, Fengrong Wang, Edmund K Waller
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 180 Issue 10 Pg. 6892-902 (May 15 2008) ISSN: 0022-1767 [Print] United States
• PMID: 18453610 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antiviral Agents
• Cytokines
• Furocoumarins
• amotosalen

Topics

• Animals
• Antiviral Agents (pharmacology)
• Bone Marrow Transplantation
• Cytokines (blood)
• Cytomegalovirus Infections (immunology, prevention & control)
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Furocoumarins (pharmacology)
• Graft Rejection (prevention & control)
• Graft vs Host Disease (prevention & control)
• Immunotherapy, Adoptive (methods)
• Lymphocyte Transfusion (methods)
• Lymphocytes (drug effects)
• Mice