300ec2f43df21e5ce38466e21bff7dd4 pmc_11125757.pdf bdbbc06293273a261534814899f4e71e761ab1b7 pmc_11125757.pdf 904aee10fab7734baa9b32c16166e3200a791b6209920a2d5020563d0bc9eed0 pmc_11125757.pdf Title: Anti-PD-L1 Immunotherapy of Chronic Virus Infection Improves Virus Control without Augmenting Tissue Damage by Fibrosis Subject: Immunotherapy with checkpoint inhibitors, albeit commonly used against tumors, is still at its infancy against chronic virus infections. It relies on the reinvigoration of exhausted T lymphocytes to eliminate virus-infected cells. Since T cell exhaustion is a physiological process to reduce immunopathology, the reinvigoration of these cells might be associated with an augmentation of pathological changes. To test this possibility, we here analyzed in the model system of chronic lymphocytic choriomeningitis virus (LCMV)-infected mice whether treatment with the checkpoint inhibitor anti-PD-L1 antibody would increase CD8 T cell-dependent fibrosis. We show that pre-existing spleen fibrosis did not worsen under conditions that increase CD8 T cell functionality and reduce virus loads suggesting that the CD8 T cell functionality increase remained below its pathogenicity threshold. These promising findings should further encourage immunotherapeutic trials against chronic virus infections. Keywords: immunotherapy; anti-PD-L1; fibrosis; chronic virus infection; LCMV Author: Valentina Casella, Paula Cebollada Rica, Jordi Argilaguet, Enric Vidal, María González-Cao, Roberto Güerri-Fernandez, Gennady Bocharov and Andreas Meyerhans Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Fri May 17 07:22:18 2024 CEST ModDate: Fri May 17 07:43:00 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 9 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3247653 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SSNIUI+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 OULEZN+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 COFTHG+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 XVHAXR+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 YRACXK+VnURWPalladioL Type 1 Custom yes yes yes 32 0 HOWKDX+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 48 0 IAFOCY+CMSY10 Type 1 Builtin yes yes yes 65 0 BBSDEQ+EURM10 Type 1 Builtin yes yes yes 70 0 PIGJPL+PalatinoLinotype CID TrueType Identity-H yes yes yes 120 0 PIGJPO+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 126 0 PIGJPK+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 129 0 PIGJPM+PalatinoLinotype TrueType WinAnsi yes yes no 132 0 PIGKGN+PalatinoLinotype TrueType MacRoman yes yes no 135 0 GMGMCA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 186 0 GMGMCB+PalatinoLinotype CID TrueType Identity-H yes yes yes 189 0 GMGMCC+PalatinoLinotype TrueType WinAnsi yes yes no 195 0 GMGMCE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 198 0 GMGMJC+PalatinoLinotype TrueType MacRoman yes yes no 201 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-02-27 02:10:19 CET RepresentationInformation: pmc_11125757.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-02-27 02:03:33 CET Size: 3247653 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 373 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Item: Title: Discussion Destination: section.3 Item: Title: Material and Methods Destination: section.4 Children: Item: Title: Mice Destination: subsection.4.1 Item: Title: Virus Infections Destination: subsection.4.2 Item: Title: In Vivo Treatments with Anti-PD-L1 Destination: subsection.4.3 Item: Title: Flow Cytometry Destination: subsection.4.4 Item: Title: Virus Load Quantification Destination: subsection.4.5 Item: Title: Histological Staining Destination: subsection.4.6 Item: Title: Quantification and Statistical Analysis Destination: subsection.4.7 Item: Title: References Destination: section.5 Info: Title: Anti-PD-L1 Immunotherapy of Chronic Virus Infection Improves Virus Control without Augmenting Tissue Damage by Fibrosis Author: Valentina Casella, Paula Cebollada Rica, Jordi Argilaguet, Enric Vidal, María González-Cao, Roberto Güerri-Fernandez, Gennady Bocharov and Andreas Meyerhans Subject: Immunotherapy with checkpoint inhibitors, albeit commonly used against tumors, is still at its infancy against chronic virus infections. It relies on the reinvigoration of exhausted T lymphocytes to eliminate virus-infected cells. Since T cell exhaustion is a physiological process to reduce immunopathology, the reinvigoration of these cells might be associated with an augmentation of pathological changes. To test this possibility, we here analyzed in the model system of chronic lymphocytic choriomeningitis virus (LCMV)-infected mice whether treatment with the checkpoint inhibitor anti-PD-L1 antibody would increase CD8 T cell-dependent fibrosis. We show that pre-existing spleen fibrosis did not worsen under conditions that increase CD8 T cell functionality and reduce virus loads suggesting that the CD8 T cell functionality increase remained below its pathogenicity threshold. These promising findings should further encourage immunotherapeutic trials against chronic virus infections. Keywords: immunotherapy; anti-PD-L1; fibrosis; chronic virus infection; LCMV Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Fri May 17 07:22:18 CEST 2024 ModDate: Fri May 17 07:43:00 CEST 2024 ID: 0x29d4b16a9baa6824d17d6adb9ea231c2, 0x29d4b16a9baa6824d17d6adb9ea231c2 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: YRACXK+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 242 FontDescriptor: FontName: YRACXK+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: OULEZN+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 252 FontDescriptor: FontName: OULEZN+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: IAFOCY+CMSY10 FontSubset: true FirstChar: 0 LastChar: 48 FontDescriptor: FontName: IAFOCY+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true ToUnicode: true Font: BaseFont: COFTHG+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: COFTHG+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: BBSDEQ+EURM10 FontSubset: true FirstChar: 12 LastChar: 22 FontDescriptor: FontName: BBSDEQ+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true ToUnicode: true Font: BaseFont: SSNIUI+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 189 FontDescriptor: FontName: SSNIUI+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: XVHAXR+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: XVHAXR+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 79, 293, 152, 302 Annotation: Subtype: Link Rect: 34, 282, 95, 290 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 125, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 149, 87 Annotation: Subtype: Link Rect: 34, 756, 147, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 127, 660, 138, 674 Annotation: Subtype: Link Rect: 244, 660, 256, 674 Annotation: Subtype: Link Rect: 429, 660, 440, 674 Annotation: Subtype: Link Rect: 161, 648, 172, 661 Annotation: Subtype: Link Rect: 276, 648, 287, 661 Annotation: Subtype: Link Rect: 419, 648, 430, 661 Annotation: Subtype: Link Rect: 234, 176, 241, 185 ActionDest: 219 Annotation: Subtype: Link Rect: 477, 151, 484, 160 ActionDest: 219 Annotation: Subtype: Link Rect: 449, 126, 456, 135 ActionDest: 219 Annotation: Subtype: Link Rect: 220, 101, 227, 110 ActionDest: 219 Annotation: Subtype: Link Rect: 542, 76, 549, 85 ActionDest: 219 Annotation: Subtype: Link Rect: 549, 76, 556, 85 ActionDest: 219 Annotation: Subtype: Link Rect: 108, 17, 237, 28 Annotation: Subtype: Link Rect: 411, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 402, 87, 421 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 530, 731, 537, 740 ActionDest: 219 Annotation: Subtype: Link Rect: 359, 718, 366, 727 ActionDest: 222 Annotation: Subtype: Link Rect: 222, 693, 229, 702 ActionDest: 222 Annotation: Subtype: Link Rect: 255, 630, 267, 639 ActionDest: 222 Annotation: Subtype: Link Rect: 410, 618, 422, 627 ActionDest: 222 Annotation: Subtype: Link Rect: 370, 605, 382, 614 ActionDest: 222 Annotation: Subtype: Link Rect: 224, 580, 236, 589 ActionDest: 222 Annotation: Subtype: Link Rect: 368, 442, 380, 451 ActionDest: 222 Annotation: Subtype: Link Rect: 404, 429, 416, 438 ActionDest: 222 Annotation: Subtype: Link Rect: 416, 429, 428, 438 ActionDest: 222 Annotation: Subtype: Link Rect: 544, 326, 551, 338 ActionDest: 75 Annotation: Subtype: Link Rect: 230, 301, 237, 313 ActionDest: 75 Annotation: Subtype: Link Rect: 506, 266, 517, 275 ActionDest: 222 Annotation: Subtype: Link Rect: 249, 251, 256, 263 ActionDest: 75 Annotation: Subtype: Link Rect: 382, 251, 389, 263 ActionDest: 75 Annotation: Subtype: Link Rect: 543, 213, 550, 225 ActionDest: 75 Annotation: Subtype: Link Rect: 225, 188, 232, 200 ActionDest: 75 Annotation: Subtype: Link Rect: 458, 176, 465, 188 ActionDest: 75 Annotation: Subtype: Link Rect: 264, 163, 271, 175 ActionDest: 75 Annotation: Subtype: Link Rect: 346, 141, 358, 150 ActionDest: 222 Page: Sequence: 3 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 422, 728, 429, 740 ActionDest: 75 Annotation: Subtype: Link Rect: 413, 691, 420, 703 ActionDest: 75 Annotation: Subtype: Link Rect: 289, 668, 301, 677 ActionDest: 222 Annotation: Subtype: Link Rect: 341, 590, 348, 602 ActionDest: 75 Annotation: Subtype: Link Rect: 525, 552, 532, 564 ActionDest: 162 Annotation: Subtype: Link Rect: 200, 527, 207, 539 ActionDest: 162 Annotation: Subtype: Link Rect: 309, 527, 316, 539 ActionDest: 162 Annotation: Subtype: Link Rect: 444, 527, 451, 539 ActionDest: 162 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 478, 678, 490, 687 ActionDest: 222 Annotation: Subtype: Link Rect: 387, 662, 394, 674 ActionDest: 75 Annotation: Subtype: Link Rect: 412, 650, 419, 662 ActionDest: 75 Annotation: Subtype: Link Rect: 370, 515, 382, 523 ActionDest: 222 Annotation: Subtype: Link Rect: 228, 464, 240, 473 ActionDest: 222 Annotation: Subtype: Link Rect: 198, 427, 210, 436 ActionDest: 222 Annotation: Subtype: Link Rect: 332, 414, 344, 423 ActionDest: 222 Annotation: Subtype: Link Rect: 362, 376, 374, 385 ActionDest: 222 Annotation: Subtype: Link Rect: 417, 364, 429, 373 ActionDest: 222 Annotation: Subtype: Link Rect: 409, 288, 421, 298 ActionDest: 222 Annotation: Subtype: Link Rect: 422, 289, 434, 298 ActionDest: 222 Annotation: Subtype: Link Rect: 214, 276, 226, 285 ActionDest: 222 Annotation: Subtype: Link Rect: 281, 263, 293, 272 ActionDest: 222 Annotation: Subtype: Link Rect: 296, 263, 308, 272 ActionDest: 222 Annotation: Subtype: Link Rect: 464, 201, 476, 210 ActionDest: 222 Annotation: Subtype: Link Rect: 477, 201, 489, 210 ActionDest: 222 Annotation: Subtype: Link Rect: 479, 175, 491, 185 ActionDest: 225 Annotation: Subtype: Link Rect: 352, 100, 364, 109 ActionDest: 225 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 288, 441, 300, 450 ActionDest: 222 Annotation: Subtype: Link Rect: 305, 264, 317, 273 ActionDest: 222 Annotation: Subtype: Link Rect: 302, 101, 314, 110 ActionDest: 222 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 476, 247, 513, 258 Annotation: Subtype: Link Rect: 520, 247, 556, 258 Annotation: Subtype: Link Rect: 433, 235, 470, 246 Annotation: Subtype: Link Rect: 477, 235, 513, 246 Annotation: Subtype: Link Rect: 95, 213, 133, 223 Annotation: Subtype: Link Rect: 139, 213, 175, 223 Annotation: Subtype: Link Rect: 467, 189, 505, 200 Annotation: Subtype: Link Rect: 511, 189, 547, 200 Annotation: Subtype: Link Rect: 154, 155, 192, 166 Annotation: Subtype: Link Rect: 198, 155, 234, 166 Annotation: Subtype: Link Rect: 311, 120, 348, 131 Annotation: Subtype: Link Rect: 354, 120, 390, 131 Annotation: Subtype: Link Rect: 104, 86, 142, 96 Annotation: Subtype: Link Rect: 148, 86, 184, 96 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 403, 730, 441, 741 Annotation: Subtype: Link Rect: 448, 706, 486, 718 Annotation: Subtype: Link Rect: 492, 706, 528, 718 Annotation: Subtype: Link Rect: 277, 672, 314, 683 Annotation: Subtype: Link Rect: 320, 672, 356, 683 Annotation: Subtype: Link Rect: 169, 650, 207, 660 Annotation: Subtype: Link Rect: 213, 650, 249, 660 Annotation: Subtype: Link Rect: 147, 615, 184, 625 Annotation: Subtype: Link Rect: 191, 615, 227, 625 Annotation: Subtype: Link Rect: 274, 592, 312, 602 Annotation: Subtype: Link Rect: 318, 592, 354, 602 Annotation: Subtype: Link Rect: 131, 558, 168, 568 Annotation: Subtype: Link Rect: 175, 558, 211, 568 Annotation: Subtype: Link Rect: 59, 523, 96, 533 Annotation: Subtype: Link Rect: 102, 523, 138, 533 Annotation: Subtype: Link Rect: 313, 488, 351, 499 Annotation: Subtype: Link Rect: 402, 476, 440, 487 Annotation: Subtype: Link Rect: 446, 476, 482, 487 Annotation: Subtype: Link Rect: 174, 443, 211, 453 Annotation: Subtype: Link Rect: 217, 443, 253, 453 Annotation: Subtype: Link Rect: 95, 420, 133, 430 Annotation: Subtype: Link Rect: 139, 420, 175, 430 Annotation: Subtype: Link Rect: 515, 396, 553, 407 Annotation: Subtype: Link Rect: 479, 384, 516, 395 Annotation: Subtype: Link Rect: 521, 384, 557, 395 Annotation: Subtype: Link Rect: 475, 373, 512, 384 Annotation: Subtype: Link Rect: 519, 373, 555, 384 Annotation: Subtype: Link Rect: 382, 350, 420, 361 Annotation: Subtype: Link Rect: 406, 327, 444, 338 Annotation: Subtype: Link Rect: 450, 327, 486, 338 Annotation: Subtype: Link Rect: 262, 304, 299, 315 Annotation: Subtype: Link Rect: 519, 269, 557, 280 Annotation: Subtype: Link Rect: 59, 259, 95, 269 Annotation: Subtype: Link Rect: 255, 224, 293, 234 Annotation: Subtype: Link Rect: 299, 224, 335, 234 Annotation: Subtype: Link Rect: 299, 200, 336, 211 Annotation: Subtype: Link Rect: 343, 200, 379, 211 Annotation: Subtype: Link Rect: 249, 167, 287, 177 Annotation: Subtype: Link Rect: 293, 167, 329, 177 Annotation: Subtype: Link Rect: 470, 143, 507, 154 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 113, 719, 150, 729 Annotation: Subtype: Link Rect: 156, 719, 192, 729 Annotation: Subtype: Link Rect: 242, 683, 280, 694 Annotation: Subtype: Link Rect: 286, 683, 322, 694 Checksum: e2a0be14 Type: CRC32 Checksum: 300ec2f43df21e5ce38466e21bff7dd4 Type: MD5 Checksum: bdbbc06293273a261534814899f4e71e761ab1b7 Type: SHA-1 Checksum: 904aee10fab7734baa9b32c16166e3200a791b6209920a2d5020563d0bc9eed0 Type: SHA-256