September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Multiplicities of Lacrimal Gland Disease Phenotypes
Author Affiliations & Notes
  • Austin K Mircheff
    Univ of Southern California, Los Angeles, California, United States
  • Yanru Wang
    Univ of Southern California, Los Angeles, California, United States
  • Joel E Schechter
    Univ of Southern California, Los Angeles, California, United States
  • Meng Li
    Univ of Southern California, Los Angeles, California, United States
  • Warren Tong
    Allergan, Irvine, California, United States
  • Mayssa Attar
    Allergan, Irvine, California, United States
  • Murty Chengalvala
    Covance Research Products, Denver, Pennsylvania, United States
  • Joe Harmuth
    Covance Research Products, Denver, Pennsylvania, United States
  • Jeffery J Prusakiewicz
    Covance Laboratories, Madison, Wisconsin, United States
  • Footnotes
    Commercial Relationships   Austin Mircheff, Allergan (F), Allergan (C); Yanru Wang, None; Joel Schechter, None; Meng Li, None; Warren Tong, Allergan (E); Mayssa Attar, Allergan (E); Murty Chengalvala, Covance Research Products (E); Joe Harmuth, Covance Research Products (E); Jeffery Prusakiewicz, Covance Laboratories (E)
  • Footnotes
    Support  Unrestricted Grant from Allergan
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 392. doi:
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      Austin K Mircheff, Yanru Wang, Joel E Schechter, Meng Li, Warren Tong, Mayssa Attar, Murty Chengalvala, Joe Harmuth, Jeffery J Prusakiewicz; Multiplicities of Lacrimal Gland Disease Phenotypes. Invest. Ophthalmol. Vis. Sci. 2016;57(12):392.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Several diagnoses are associated with lacrimal gland dysfunction and dry eye disease, but the recognized immunopathologies do not account for the known spectrum of histopathological presentations. As the existence of unrecognized disease phenotypes may hinder design and testing of therapeutics, we devised new protocols for inducing lacrimal gland disease models in rabbits and a new approach to assessing disease phenotype diversity.

Methods : A gland lysate post-nuclear membrane fraction was used to immunize rabbits. Microparticles (exosomes, MP) secreted by primary acinar cells were isolated from supernatant media and loaded into bone marrow monocyte-derived dendritic cells (mDC). Peripheral blood lymphocytes (PBL) were activated in ex vivo mixed cell reactions with LPS-stimulated, MP-loaded mDC. Activated PBL were used to transfer disease to autologous lacrimal glands (primary adoptively transferred disease, 1°ATD). Glands were profiled for T cell- and bone marrow-derived cell numbers, immune response-related gene transcript abundances, and atrophy. Principal Component Analysis (PCA) was used to form hypotheses for immune cell- and epithelial cell functional clusters determining normal- and disease phenotypes.

Results : Adoptive transfer to naïve animals, systemic immunization, and adoptive transfer to systemically immunized animals led to a variety of disease phenotypes. The most severe developed in 1°ATD glands of animals that had been systemically immunized. PCA suggested that the major source of variation among these was the balance between two competing functional clusters, one comprising cells that, collectively, expressed CD4, perforin, and IL-17A, the other comprising cells that, collectively, expressed CD8, TNF-α, IL-1, IL-18, and MMP-9. Perforin- and IL-17A-expressing functional clusters were strongly associated with increasing atrophy; development of such clusters was related to robustness of cellular autoimmune responses, rather than humoral autoimmune responses, elicited by systemic immunization.

Conclusions : The newly-devised protocols are suitable for large-scale studies. Each induces a diversity of disease phenotypes, which may be described as combinatorial products of distinct immune cell functional clusters. Characterization of predominant pathological functional clusters may reveal new therapeutic targets. Prospectively stratifying study participants according to disease phenotype may improve clinical trial outcomes.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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