Mitomycin C-treated antigen-presenting cells as a tool for control of allograft rejection and autoimmunity: from bench to bedside.
Cells have been previously used in experimental models for tolerance induction in organ transplantation and autoimmune diseases. One problem with the therapeutic use of cells is standardization of their preparation. We discuss an immunosuppressive strategy relying on cells irreversibly transformed by a chemotherapeutic drug. Dendritic cells (DCs) of transplant donors pretreated with mitomycin C (MMC) strongly prolonged rat heart allograft survival when injected into recipients before transplantation. Likewise, MMC-DCs loaded with myelin basic protein suppressed autoreactive T cells of MS patients in vitro and prevented experimental autoimmune encephalitis in mice. Comprehensive gene microarray analysis identified genes that possibly make up the suppressive phenotype, comprising glucocorticoid leucine zipper, immunoglobulin-like transcript 3, CD80, CD83, CD86, and apoptotic genes. Based on these findings, a hypothetical model of tolerance induction by MMC-treated DCs is delineated. Finally, we describe the first clinical application of MMC-treated monocyte-enriched donor cells in an attempt to control the rejection of a haploidentical stem cell transplant in a sensitized recipient and discuss the pros and cons of using MMC-treated antigen-presenting cells for tolerance induction. Although many questions remain, MMC-treated cells are a promising clinical tool for controlling allograft rejection and deleterious immune responses in autoimmune diseases.
Terness
Peter
P
Institute of Immunology, University of Heidelberg, Department of Transplantation Immunology, Heidelberg, Germany. peter.terness@med.uni-heidelberg.de
Kleist
Christian
C
Simon
Helmut
H
Sandra-Petrescu
Flavius
F
Ehser
Sandra
S
Chuang
Jing-Jing
JJ
Mohr
Elisabeth
E
Jiga
Lucian
L
Greil
Johann
J
Opelz
Gerhard
G
D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D017209:Apoptosis / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy; D015551:Autoimmunity / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000637:transplantation; D006084:Graft Rejection / Q000276:immunology* / Q000628:therapy; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D018448:Models, Immunological; D016377:Organ Transplantation / Q000379:methods; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D016685:Mitomycin