Unique features and clinical importance of acute alloreactive immune responses

Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation

Human macrophage inflammatory protein-3α/CCL20/LARC/Exodus/SCYA20 is transcriptionally upregulated by tumor necrosis factor-α via a non-standard NF-κB site

AbstractThe 5′-flanking sequences of the human macrophage inflammatory protein-3α/CCL20 gene were cloned and transfected into G-361 human melanoma cells in a luciferase reporter construct. Tumor necrosis factor-α (TNF-α) treatment stimulated luciferase expression, and promoter truncations demonstrated that TNF-α inducibility is conferred by a region between nt −111 and −77, which contains a non-standard nuclear factor-κB (NF-κB) binding site. The requirement for NF-κB was demonstrated as follows: (i) mutations in this NF-κB site abrogated TNF-α responsiveness; (ii) TNF-α activated a construct containing two copies of the CCL20 NF-κB binding site; (iii) overexpression of NF-κB p65 activated the CCL20 promoter; (iv) NF-κB from nuclear extracts of TNF-α-stimulated cells bound specifically to this NF-κB site