Paramunity-inducing Factors (PINDs) in dendritic cell (DC) cultures lead to impaired antileukemic functionality of DC-stimulated T-cells

Christian Ansprenger; Valentin Vogt; Julia Schick; Annika Hirn-Lopez; Yvonne Vokac; Ihor Harabacz; Marion Braeu; Tanja Kroell; Axel Karenberg; Hans-Jochem Kolb; Helga Schmetzer

doi:10.1016/j.cellimm.2018.03.005

Paramunity-inducing Factors (PINDs) in dendritic cell (DC) cultures lead to impaired antileukemic functionality of DC-stimulated T-cells

Cell Immunol. 2018 Jun:328:33-48. doi: 10.1016/j.cellimm.2018.03.005. Epub 2018 Mar 16.

Authors

Affiliations

¹ Dept for Hematopoetic Transplantations, MED3, University of Munich, Germany.
² VironPearl Biotech GmbH, Munich, Germany.
³ Helmholtz Center Munich, CCG-HCT, Munich, Germany.
⁴ Institute for the History of Medicine and Medical Ethics, University of Cologne, Germany.
⁵ Dept for Hematopoetic Transplantations, MED3, University of Munich, Germany; Helmholtz Center Munich, CCG-HCT, Munich, Germany. Electronic address: Helga.Schmetzer@med.uni-muenchen.de.

PMID: 29580554
DOI: 10.1016/j.cellimm.2018.03.005

Abstract

Introduction: Paramunity-inducing-Factors (PINDs) consist of attenuated/inactivated viruses of various poxvirus-genera, used in veterinary medicine as non-antigen-specific, non-immunising stimulators of the innate immune system against infectious and malignant diseases. Their danger-signaling-interactions were tested for their capacity to improve leukemic antigen-presentation on DC generated from AML-patients' blasts ('DC_leu') and DC-stimulation/activation of antileukemic T-cells.

Methods: We analyzed, whether the addition of PINDs during DC cultures (15 healthy, 22 leukemic donors) and mixed lymphocyte culture (MLC, n = 15) with autologous (n = 6), allogeneic (n = 2) or T-cells after stem cell transplantation (SCT; n = 7) would alter the quality and quantity of DC, the composition of T-cell-subsets, and/or their antileukemic functionality (AF) as studied by FACS and functional Fluorolysis-cytotoxicity-assays.

Results: Effects on 1. DC-cultures: PINDs in DC-cultures lead to increased proportions of mature DC and DC_leu, but reduced proportions of viable and overall, as well as TLR4- and TLR9-expressing DC. 2. MLC: PINDs increased early (CD8+) T-cell activation (CD69+), but reduced proportions of effector-T-cells after MLC 3. AF: Presence of PINDs in DC- and MLC-cultures reduced T-cells' as well as innate cells' antileukemic functionality. 4. Cytokine-release profile: Supernatants from PIND-treated DC- and MLC-cultures resembled an inhibitory microenvironment, correlating with impaired blast lysis.

Conclusions: Our data shows that addition of PINDs to DC-cultures and MLC result in a "blast-protective-capacity" leading to impaired AF, likely due to changes in the composition of T-/innate effector cells and the induction of an inhibitory microenvironment. PINDs might be promising in treating infectious diseases, but cannot be recommended for the treatment of AML-patients due to their inhibitory influence on antileukemic functionality.

Keywords: AML; Dendritic cells; Immunotherapy; PIND; Paramunity; T-cells; Zylexis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antigen Presentation / immunology
Antigens, CD / immunology
Biological Products / pharmacology*
Cell Culture Techniques / methods
Cytotoxicity, Immunologic / immunology
Dendritic Cells / immunology*
Female
Flow Cytometry
Humans
Immunophenotyping
Lymphocyte Activation / immunology*
Lymphocyte Culture Test, Mixed / methods
Male
T-Lymphocyte Subsets / immunology

Substances

Antigens, CD
Biological Products
PIND-AVI