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Upregulation of Class I Major Histocompatibility Complex Antigens Proc. Natl. Acad. Sci. USA Vol. 92, pp. 7257-7261, August 1995 Immunology Upregulation of class I major histocompatibility complex antigens by interferon y is necessary for T-cell-mediated elimination of recombinant adenovirus-infected hepatocytes in vivo YIPING YANG*t, ZHIQUAN XIANGt, HILDEGUND C. J. ERTLt, AND JAMES M. WILSON*t# *Institute for Human Gene Therapy and Departments of Medicine and Molecular and Cellular Engineering, the University of Pennsylvania, and tthe Wistar Institute, Philadelphia, PA 19104-4268 Communicated by Robert Austrian, University ofPennsylvania, Philadelphia, PA, March 30, 1995 (received for review January 30, 1995) ABSTRACT Recombinant adenoviruses are attractive ve- mediated destruction through upregulation of major histocom- hicles for liver-directed gene therapy because of the high patibility complex (MHC) class I expression. efficiency with which they transfer genes to hepatocytes in vivo. First generation recombinant adenoviruses deleted of El sequences also express recombinant and early and late viral MATERIALS AND METHODS genes, which lead to development of destructive cellular Animals. C57BL/6 mice (H-2b) were obtained from The immune responses. Previous studies indicated that class I Jackson Laboratory. MHC class II-deficient mice were pur- major histocompatibility complex (MHC)-restricted cytotoxic chased from GenPharm International (Mountain View, CA). T lymphocytes (CTLs) play a major role in eliminating IFN-y-deficient mice were obtained from Genentech. CD4- virus-infected cells. The present studies utilize mouse models and perforin-deficient mice were kindly provided by Barbara to evaluate the role of T-helper cells in the primary response Knowles (The Jackson Laboratory) and William Clark (Uni- to adenovirus-mediated gene transfer to the liver. In vivo versity of California, Los Angeles), respectively. MHC class ablation of CD4+ cells or interferon 'y (IFN-y) was sufficient II-deficient, IFN-y-deficient, CD4-, and perforin-deficient to prevent the elimination of adenovirus-transduced hepato- mice were bred onto the C57BL/6 background. CD4+ T cells cytes, despite the induction of a measurable CTL response. and IFN-,ywere depleted by inoculating mice intraperitoneally Mobilization of an effective THI response as measured by in with 0.5-ml aliquots of a 1:10 dilution of mouse ascites fluid vitro proliferation assays was associated with substantial containing the GK1.5 (anti-CD4; American Type Culture upregulation of MHC class I expression, an effect that was Collection) and XMG1.2 (anti-IFN--y; American Type Culture prevented in IFN-y-deficient animals. These results suggest Collection) monoclonal antibody (mAb). For depletion of that elimination of virus-infected hepatocytes in a primary CD4+ cells, the mAb was given 3 days before, on the day of exposure to recombinant adenovirus requires both induction infection, 3 days after, and then at 3-day intervals until of antigen-specific CTLs as well as sensitization of the target completion of the experiment; for depletion of IFN-y, the cell by TH1-mediated activation of MHC class I expression. mAb was administered 3 days before, 3 days after, and then at 6-day intervals until completion of the experiment. Human type C adenoviruses have been rendered replication Recombinant Adenoviruses. The recombinant adenoviruses defective for gene therapy by deleting the first early gene locus H5.OOCMVlacZ [lacZ gene expressed from the cytomegalovirus that encodes Ela and Elb. An extensive literature has (CMV) promoter in the sub360 backbone] and H5.01OCBALP emerged demonstrating the utility of El-deleted viruses for (alkaline phosphatase gene expressed from the CMV-enhanced accomplishing efficient gene transfer in a variety of cells in vivo (3-actin promoter in the sub360 backbone) were used in this study. (1). In most models, recombinant gene expression has been Virus (2 x 109 plaque-forming units in 100 ,ul of phosphate- transient, lasting less than 3-4 weeks, and associated with buffered saline) was administered into female mice (6-8 weeks development of inflammation characterized by lymphocytic old) via the tail vein. When mice were necropsied 3, 10, or 24 days infiltrates. Our work in murine models indicates that El- later, liver tissues were prepared for cryosections, while spleens deleted adenoviruses express viral proteins and potentially were harvested for immunological assays. immunogenic recombinant proteins that elicit destructive class Morphological Analyses. Histochemistry. Sections of fresh I-restricted cytotoxic T lymphocytes (CTLs) (refs. 2 and 3; data frozen tissue (6 ,um) were fixed in 0.5% glutaraldehyde and not shown). Immune-mediated clearance of the corrected cell analyzed for expression of 13-galactosidase or alkaline phos- could explain the limitations of transient expression and phatase histochemistry as described (3). pathology that characterized first generation adenoviral tech- Immunofluorescence. Frozen sections (6 ,um) were fixed in nology. Humoral immune responses to proteins of the input methanol. CD4+/CD8+ double immunofluorescence was per- recombinant adenovirus underlie an unrelated but equally formed as described (4). For MHC class I staining, sections important problem of neutralizing antibodies that prevent were incubated with 1:10 diluted mouse hybridoma superna- gene transfer upon a second administration of virus (3). tant to H-2KbDb (20-8-4S) for 60 min, followed by incubation This study uses a mouse model of adenovirus-mediated gene with goat anti-mouse IgG-conjugated fluorescein isothiocya- transfer to liver to define the precise cellular immune re- nate (FITC) (5 ,tg/ml) for 30 min. Sections were washed and sponses responsible for destruction of the genetically modified mounted with the antifadent Citifluor (Canterbury Chemical hepatocytes. Data presented here show that CD4+ cells work Lab., Canterbury, U.K.). in concert with virus-activated CTLs to eliminate the target CTL Assays. CTL assays were performed with splenocytes cells. This occurs, in part, through activation of T-helper cells pooled from three mice as described (2). Briefly, splenocytes of the THI subset and secretion of interferon -y (IFN-,y), which were restimulated in vitro for 5 days with H5.OlOCMVlacZ and sensitizes the genetically modified hepatocyte to CTL- Abbreviations: CTL, cytotoxic T lymphocyte; IFN-,y, interferon y; The publication costs of this article were defrayed in part by page charge MHC, major histocompatibility complex; mAb, monoclonal antibody; payment. This article must therefore be hereby marked "advertisement" in IL, interleukin. accordance with 18 U.S.C. §1734 solely to indicate this fact. iTo whom reprint requests should be addressed. 7257 Downloaded by guest on September 28, 2021 7258 Immunology: Yang et aL Proc. Natl. Acad. Sci. USA 92 (1995) assayed on MHC-compatible, 51Cr-labeled, H5.OlOCMVlacZ class I-compatible targets infected with the recombinant virus infected, C57SV (H-2b) cells using different effector/target or another recombinant virus expressing a different transgene. cell ratios. Percentage specific 51Cr release was calculated as Animals deficient in MHC class I and CD8+ cells by virtue of described (2). a germ-line interruption of f32-microglobulin failed to elimi- Cytokine Release Assays. Interleukin (IL)-2 and IL-4 release nate transduced hepatocytes. In addition, adoptive transfer of assay. Splenocytes were restimulated in vitro with UV- activated and purified CD8+ cells into an adenovirus-trans- inactivated H5.OlOCMVlacZ for 24 hr. Cell-free supernatants duced RAG-2-deficient mouse was sufficient to eliminate the were assayed for the presence of IL-2 or IL-4 on HT-2 cells (an transgene-expressing hepatocytes. IL-2- or IL-4-dependent cell line) as described (2); the relative The function and relative importance of CTLs in adenovi- contribution of each cytokine to stimulation of HT-2 was rus-mediated gene transfer to mouse liver were further eval- assessed by specific neutralization of either IL-2 or IL-4 with uated in the current study by using mice genetically deficient mAbs. in perforin (11), a molecule that mediates one mechanism of IFN-,y release assay. The presence of IFN-,y in the same CTL killing (12). Perforin-deficient mice were injected with splenocyte culture supernatant was measured as described (2). the lacZ adenovirus and liver tissue was analyzed for stability of transgene expression and infiltration of lymphocytes (Fig. RESULTS AND DISCUSSION 1). Congenic immune-competent animals developed a mixed CD4+ and CD8+ lymphocytic infiltrate in liver (Fig. lc), while First generation recombinant adenoviruses were developed for expression of the transgene diminished to undetectable levels gene therapy based on the premise that deletion of El by day 24 (Fig. lb); this is in contrast to the perforin-deficient sequences should be sufficient to inactivate other viral genes animals who did not eliminate significant numbers of trans- and render the virus replication defective. Previous in vitro duced hepatocytes (Fig. le) despite mobilizing a full CD4+ and studies suggested that this is not the case when infections are CD8+ lymphocyte response (Fig. lf). This same animal model performed under high multiplicity of infection or in hepato- in cyte-derived cells where El transcription-like factors, such as has been used to demonstrate the importance of perforin NF-IL-6, are abundant (5). Studies in a variety of preclinical CTL-mediated destruction of cells infected with lymphocytic models including
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