TY - JOUR
T1 - Development and Characterization of a Preclinical Model for the Evaluation of CD205-Mediated Antigen Delivery Therapeutics in Type 1 Diabetes
AU - Schloss, Jennifer
AU - Ali, Riyasat
AU - Babad, Jeffrey
AU - Guerrero-Ros, Ignacio
AU - Pongsachai, Jillamika
AU - He, Li Zhen
AU - Keler, Tibor
AU - DiLorenzo, Teresa P.
N1 - Funding Information:
Received for publication March 4, 2019. Accepted for publication June 7, 2019. Address correspondence and reprint requests to: Dr. Teresa P. DiLorenzo, Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Room 403, Bronx, NY 10461. E-mail address: teresa.dilorenzo@einstein.yu.edu. ORCIDs: 0000-0001-6739-0902 (J.S.); 0000-0003-4022-276X (R.A.); 0000-0002-2586-1371 (J.B.); 0000-0003-2294-9092 (I.G.-R.); 0000-0001-8206-761X (L.-Z.H.); 0000-0003-4337-3598 (T.P.D.). This work was supported by National Institutes of Health R01 DK064315, R01 DK094327, R03 AI119225, R01 AI123730, and R01 DK120420 (to T.P.D.), F30 DK103368 (to J.S.), T32 GM007288 (which supported J.S.), P30 CA013330 (to the Cancer Center of the Albert Einstein College of Medicine), P30 DK020541 (to the Einstein-Mount Sinai Diabetes Research Center), the American Diabetes Association (1-16-IBS-069 to T.P.D.), and by grants from the Iacocca Family Foundation and the Diabetes Action Research and Education Foundation (to T.P.D.). J.P. was supported by the Diversity Student Summer Research Opportunity Program of the Albert Einstein College of Medicine. T.P.D. is the Diane Belfer, Cypres & Endelson Families Faculty Scholar in Diabetes Research. Abbreviations used in this article: BMDC, bone marrow–derived DC; cDC, classical DC; CHO, Chinese hamster ovary; DC, dendritic cell; hCD205, human CD205; hIns, human proinsulin; Ins2, murine proinsulin 2; mCD205, murine CD205; MHC II, class II MHC; MoDC, monocyte-derived DC; pDC, plasmacytoid DC; RPMI-10, RPMI 1640 containing 10% FBS, 50 U/ml penicillin and 50 mg/ml streptomycin, 1 mM sodium pyruvate, and 1⨯ nonessential amino acids; T1D, type 1 diabetes. The online version of this article contains supplemental material. This article is distributed under the terms of the CC BY-NC-ND 4.0 Unported license. Copyright © 2019 The Authors
Publisher Copyright:
Copyright © 2019 The Authors
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Dendritic cells (DCs) are crucial for the production of adaptive immune responses to disease-causing microbes. However, in the steady state (i.e., in the absence of an infection or when Ags are experimentally delivered without a DC-activating adjuvant), DCs present Ags to T cells in a tolerogenic manner and are important for the establishment of peripheral tolerance. Delivery of islet Ags to DCs using Ag-linked Abs to the DC endocytic receptor CD205 has shown promise in the NOD mouse model of type 1 diabetes (T1D). It is important to note, however, that all myeloid DCs express CD205 in humans, whereas in mice, only one of the classical DC subsets does (classical DC1; CD8α+ in spleen). Thus, the evaluation of CD205-targeted treatments in mice will likely not accurately predict the results observed in humans. To overcome this challenge, we have developed and characterized a novel NOD mouse model in which all myeloid DCs transgenically express human CD205 (hCD205). This NOD.hCD205 strain displays a similar T1D incidence profile to standard NOD mice. The presence of the transgene does not alter DC development, phenotype, or function. Importantly, the DCs are able to process and present Ags delivered via hCD205. Because Ags taken up via hCD205 can be presented on both class I and class II MHC, both CD4+ and CD8+ T cells can be modulated. As both T cell subsets are important for T1D pathogenesis, NOD.hCD205 mice represent a unique, patient-relevant tool for the development and optimization of DC-directed T1D therapies.
AB - Dendritic cells (DCs) are crucial for the production of adaptive immune responses to disease-causing microbes. However, in the steady state (i.e., in the absence of an infection or when Ags are experimentally delivered without a DC-activating adjuvant), DCs present Ags to T cells in a tolerogenic manner and are important for the establishment of peripheral tolerance. Delivery of islet Ags to DCs using Ag-linked Abs to the DC endocytic receptor CD205 has shown promise in the NOD mouse model of type 1 diabetes (T1D). It is important to note, however, that all myeloid DCs express CD205 in humans, whereas in mice, only one of the classical DC subsets does (classical DC1; CD8α+ in spleen). Thus, the evaluation of CD205-targeted treatments in mice will likely not accurately predict the results observed in humans. To overcome this challenge, we have developed and characterized a novel NOD mouse model in which all myeloid DCs transgenically express human CD205 (hCD205). This NOD.hCD205 strain displays a similar T1D incidence profile to standard NOD mice. The presence of the transgene does not alter DC development, phenotype, or function. Importantly, the DCs are able to process and present Ags delivered via hCD205. Because Ags taken up via hCD205 can be presented on both class I and class II MHC, both CD4+ and CD8+ T cells can be modulated. As both T cell subsets are important for T1D pathogenesis, NOD.hCD205 mice represent a unique, patient-relevant tool for the development and optimization of DC-directed T1D therapies.
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U2 - 10.4049/immunohorizons.1900014
DO - 10.4049/immunohorizons.1900014
M3 - Article
AN - SCOPUS:85128868057
VL - 3
SP - 236
EP - 253
JO - ImmunoHorizons
JF - ImmunoHorizons
SN - 2573-7732
IS - 6
ER -