title: A chronic renal rejection model with a fully MHC-mismatched rat strain combination under immunosuppressive therapy.
abstract: The Fischer-to-Lewis (LEW) rat model of kidney transplantation is a widely accepted and well-characterized model of chronic rejection. In contrast to transplantation in a clinical setting, however, the absence of treatment with immunosuppressants and only minor mismatch of major histocompatibility complexes (MHCs) are critical discrepancies. Here, we established a rat model of chronic rejection using fully MHC-mismatched strains in which kidney disease progresses even under immunosuppressive therapy.
  
  
  
  LEW (RT1(l)) rats were used as donors and Brown Norway (BN, RT1(n)) rats as recipients. Intramuscular administration of 0.1mg/kg of tacrolimus was initiated on the day of transplantation. Post-transplantation, this dose was maintained until Day 9, suspended until Day 28 and then resumed from Day 29. Renal function, histopathology, and levels of donor-specific antibody (DSA) and several biomarkers of renal injury were assessed.
  
  
  
  On Day 91 post-transplantation, recipients received tacrolimus treatment with short-term suspension exhibited reduced renal function and changes in histology. Those were characteristics of chronic rejection including glomerulosclerosis, interstitial fibrosis, and tubular atrophy in human transplantation recipients. Urinary protein excretion increased in a linear fashion, and elevated levels of several biomarkers of renal injury and DSA were observed even under administration of an immunosuppressant.
  
  
  
  We established an allograft rejection model with impaired renal function and typical histopathological changes of chronic rejection in fully MHC-mismatched rats by controlling administration of an immunosuppressant. These findings suggest that this model more accurately reflects transplantation in a clinical setting than existing models and enables the evaluation of therapeutic agents.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: kaori.hanaoka@astellas.com.
authors.forename: Kaori
authors.initials: K
authors.lastname: Hanaoka
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: yuka.kawato@astellas.com.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kawato
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: kaori.kubo@astellas.com.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kubo
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: tnakanishi@cc.miyazaki-u.ac.jp.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Nakanishi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: masashi.maeda@astellas.com.
authors.forename: Masashi
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: koji.nakamura@astellas.com.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: jun.hirose@astellas.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Hirose
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: takahisa.noto@santen.co.jp.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noto
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: hidehiko.fukahori@astellas.com.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Fukahori
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: akihiko.fujikawa@astellas.com.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Fujikawa
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: sosuke.miyoshi@astellas.com.
authors.forename: Sosuke
authors.initials: S
authors.lastname: Miyoshi
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: shoji.takakura@astellas.com.
authors.forename: Shoji
authors.initials: S
authors.lastname: Takakura
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: tatsuaki.morokata@astellas.com.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Morokata
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. Electronic address: yasuyuki.higashi@astellas.com.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Higashi
mesh_terms: D000818:Animals; D001284:Atrophy; D015415:Biomarkers / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005355:Fibrosis; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007518:Isoantibodies / Q000097:blood; D007668:Kidney / Q000276:immunology / Q000473:pathology*; D016030:Kidney Transplantation; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D012598:Sclerosis; D016559:Tacrolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; D006649:Histocompatibility Antigens; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D016559:Tacrolimus
keywords: A fully MHC-mismatched strain combination; Donor-specific antibody; Kidney transplantation