Emergence of T cells that recognize nonpolymorphic antigens during graft-versus- host disease. Blood 2012 Jun 28;119(26):6354-64
Date
04/13/2012Pubmed ID
22496151Pubmed Central ID
PMC3383195DOI
10.1182/blood-2012-01-401596Scopus ID
2-s2.0-84863508785 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
Chronic GVHD is a major cause of morbidity and mortality in allogeneic stem cell transplantation recipients and typically develops from antecedent acute GVHD. In contrast to acute GVHD, chronic GVHD has much broader tissue involvement and clinical manifestations that bear striking similarity to what is observed in autoimmune diseases. How autoimmunity arises out of alloimmunity has been a longstanding unresolved issue. To address this question, in the present study, we performed a comprehensive analysis of the clonotypic T-cell response using complementary murine models that simulate what occurs during the transition from acute to chronic GVHD. These studies revealed repertoire skewing and the presence of high-frequency clonotypes that had undergone significant in vivo expansion, indicating that GVHD-associated autoimmunity was characterized by antigen-driven expansion of a limited number of T-cell clones. Furthermore, we observed that T cells with identical TCRβ CDR3 nucleotide sequences were capable of recognizing donor and host antigens, providing evidence that the loss of self-tolerance during acute GVHD leads to the emergence of self-reactive donor T cells that are capable of recognizing nonpolymorphic tissue or commensally derived antigens. These data provide a mechanistic framework for how autoimmunity develops within the context of preexisting GVHD and provide additional insight into the pathophysiology of chronic GVHD.
Author List
Rangarajan H, Yassai M, Subramanian H, Komorowski R, Whitaker M, Gorski J, Drobyski WRAuthor
William R. Drobyski MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntigens
Autoimmunity
Base Sequence
Cell Proliferation
Colon
Epitopes, T-Lymphocyte
Genes, T-Cell Receptor beta
Graft vs Host Disease
High-Throughput Nucleotide Sequencing
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Models, Biological
T-Cell Antigen Receptor Specificity
T-Lymphocytes
