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Host and Donor Immune Responses Contribute to Antiviral Effects of Amotosalen-Treated Donor Lymphocytes following Early Posttransplant Cytomegalovirus Infection¹

Mohammad S. Hossain^*, John D. Roback, Fengrong Wang^* and Edmund K. Waller^2,*

^* Department of Hematology and Oncology, Division of Stem Cell and Bone Marrow Transplantation, Winship Cancer Institute and Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322

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/6CB6F1 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 10⁶ 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 10⁶ 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- and TNF- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by National Institutes of Health Grants HL70997 (to J.D.R.) and CA-74364 (to E.K.W.).

² Address correspondence and reprint requests to Dr. Edmund K. Waller, Department of Hematology and Oncology, Winship Cancer Institute, Emory University, 1701 Upper Gate Drive, WCI Building, 4th Floor, Atlanta, GA 30322. E-mail address: ewaller{at}emory.edu

³ Abbreviations used in this paper: GvHD, graft-vs-host disease; aGvHD, acute GvHD; BM, bone marrow; BMT, bone marrow transplant; DN, double negative; Lm, Listeria monocytogenes; MCMV, murine CMV; TCD, CD3⁺ T cell depleted.