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(Journal of Leukocyte Biology. 2002;72:1054-1062.)
© 2002 by Society for Leukocyte Biology

Molecular profiling of the role of the NF-B family of transcription factors during alloimmunity

Patricia W. Finn^*,, Hongzhen He^*,, Chunyan Ma^,, Thomas Mueller^,, James R. Stone, Hsiou-Chi Liou^||, Mark R. Boothby^# and David L. Perkins^,

^* Pulmonary Division,
Laboratory of Molecular Immunology, and Departments of
Medicine and
Pathology, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts;
^|| Graduate School of Medical Sciences, Weill Medical College, Cornell University Medical Center, New York, New York; and
^# Department of Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee

Correspondence: David L. Perkins, Brigham & Women’s Hospital, PBB-170, 75 Francis St., Boston, MA 02115. E-mail: dperkins{at}rics.bwh.harvard.edu

Allograft rejection involves a complex network of multiple immune regulators and effector mechanisms. In the current study, we focused on the role of nuclear factor (NF)-B/Rel. Previous studies had established that deficiency of the p50 NF-B family member prolonged allograft survival only modestly. However, because of its crucial role in signal transduction in inflammatory and immune responses, we hypothesized that other NF-B/Rel family members may produce more profound effects on alloimmunity. Therefore, in addition to p50, we analyzed the role of c-Rel, which is expressed predominantly in lymphocytes. Also, to investigate NF-B activation in T cells, we examined transgenic mice that express a transdominant inhibitor of NF-B [IB(N)] regulated by a T cell-restricted promoter. Allograft survival was prolonged indefinitely in the c-Rel-deficient and IB(N)-transgenic recipients. To determine the molecular basis of NF-B modulation of rejection, we analyzed a panel of 58 parameters including effector molecules, chemokines, cytokines, receptors, and cellular markers using hierarchical clustering algorithms and self-organizing maps in p50^-/-, c-Rel^-/-, and IB(N)-transgenic, experimental groups plus allogeneic-, syngeneic-, and lymphocyte-deficient (alymphoid) control groups. Surprisingly, profiles of gene expression in the c-Rel recipients (which have indefinite graft survival) were similar to the p50^-/- and allogeneic recipients (which rapidly reject grafts). As expected, gene expression in the IB(N) recipients (which also have indefinite graft survival) was similar to profiles of nonrejecting syngeneic and alymphoid recipients. Importantly, self-organizing maps identified a small subset of genes including several chemokine receptors and cytokines with expression profiles that correlate with graft survival. Thus, our results demonstrate a crucial role for NF-B in acute allograft rejection, identify different molecular mechanisms of rejection by distinct NF-B family members, and identify a small subset of inducible genes whose inhibition is linked to graft acceptance.

Key Words: transplantation • chemokines • cytokines • CD8 T cells

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