Graft rejection mediated by CD4+ T cells via indirect recognition of alloantigen is associated with a dominant Th2 response.

CD4(+) T cells that respond to indirectly presented alloantigen have been shown to mediate chronic rejection, however, the role of the indirect pathway in acute rejection has yet to be completely elucidated. To this end, BALB/c or C57BL/6 mice were depleted of CD8(+) T cells and transplanted with class II transactivator (CIITA)-deficient cardiac allografts, which cannot directly present class II alloantigens to CD4(+) T cells. In this manner, the rejection response by CD4(+) cells was forced to rely upon the indirect recognition pathway. When not depleted of CD8(+) cells, both BALB/c and C57BL/6 mice rejected CIITA-/- allografts and a polarized Th1 response was observed. In contrast, when BALB/c recipients of CIITA-/- allografts were depleted of CD8(+) T cells, the grafts were acutely rejected and a strong Th2 response characterized by eosinophil influx into the graft was observed. Interestingly, CD8-depleted C57BL/6 recipients of CIITA-/- allografts did not acutely reject their transplants and a Th2 response was not mounted. These findings indicate that CD4(+) T cells responding to indirectly presented alloantigens mediate graft rejection in a Th2-dominant manner, and provide further evidence for the role of Th2 responses in acute graft rejection.

Requirement for donor and recipient CD40 expression in cardiac allograft rejection: induction of Th1 responses and influence of donor-derived dendritic cells.

Costimulation through the CD40-CD40 ligand (CD40L) pathway is critical to allograft rejection, in that anti-CD40L mAb therapy prolongs allograft survival. However, the majority of studies exploring CD40-CD40L interactions have targeted CD40L. Less is known about the requirement for donor- and/or host-derived CD40 during rejection. This study assessed the relative contributions of donor and recipient CD40 expression to the rejection process. As the effectiveness of costimulatory blockade may be mouse strain dependent, this study explored the requirement for donor and recipient CD40 expression in BALB/c and C57BL/6 mice. Wild-type (WT) and CD40(-/-) BALB/c recipients readily rejected WT and CD40(-/-) C57BL/6 allografts, and rejection was associated with a prominent Th1 response. In contrast, CD40(-/-) C57BL/6 recipients failed to reject WT or CD40(-/-) BALB/c allografts and did not mount Th1 or Th2 responses. However, injection of donor CD40(-/-) dendritic cells induced both Th1 and Th2 responses and allograft rejection in CD40(-/-) C57BL/6 recipients. Finally, WT C57BL/6 mice rejected CD40(-/-) allografts, but this rejection response was associated with muted Th1 responses. These findings demonstrate that 1) CD40 expression by the recipient or the graft may impact on the immune response following transplantation; 2) the requirement for CD40 is influenced by the mouse strain; and 3) the requirement for CD40 in rejection may be bypassed by donor DC. Further, as CD40 is not required for rejection in BALB/c recipients, but anti-CD40L mAb prolongs graft survival in these mice, these results suggest that anti-CD40L therapy functions at a level beyond disruption of CD40-CD40L interactions.

Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis: implications for metastasis.

The transcription factor nuclear factor kappaB (NFkappaB) is constitutively active in many types of cancercells and regulates the expression of several antiapoptotic genes. Previous studies demonstrated a role for the inhibition of NFkappaB in cancer therapyusing a transgenic approach in mice. We found that NFkappaB was transiently activated much greater than background constitutive levels during colon cancer cell readhesion, which rendered the readhering colon cancer cells exquisitely susceptible to apoptosis in the presence of soluble NFkappaB inhibitors. These compounds greatly reduced colon cancer cell implantation in an in vivo seeding model of metastasis. The ability of soluble NFkappaB inhibitors to significantly induce apoptosis of readherent colon cancer cells makes them prospective candidates for preventing colon cancer metastasis.

The immunobiology of inductive anti-CD40L therapy in transplantation: allograft acceptance is not dependent upon the deletion of graft-reactive T cells.

CD40-CD40L costimulatory interactions are crucial for allograft rejection, in that treatment with anti-CD40L mAb markedly prolongs allograft survival in several systems. Recent reports indicate that costimulatory blockade results in deletion of graft-reactive cells, which leads to allograft tolerance. To assess immunologic parameters that were influenced by inductive CD40-CD40L blockade, cardiac allograft recipients were treated with multiple doses of the anti-CD40L mAb MR1, which was remarkably effective at prolonging allograft survival. Acute allograft rejection responses such as IL-2 producing helper cell priming, Th1 priming, and alloantibody production were abrogated by anti-CD40L treatment. Interestingly, the spleens of mice bearing long-term cardiac allografts following inductive anti-CD40L treatment retained precursor donor alloantigen-reactive CTL, IL-2 producing helper cells, and Th1 in numbers comparable to those observed in naïve mice. These mice retained the ability to reject donor-strain skin allografts, but were incapable of rejecting the original cardiac allograft, or a second donor-strain cardiac allograft. Further, differentiated effector cells were incapable of mediating rejection following adoptive transfer into mice bearing long-term allografts, suggesting that regulatory cell function, rather than effector cell deletion was responsible for long-term graft acceptance. Collectively, these data demonstrate that inductive CD40-CD40L blockade does not result in the deletion of graft-reactive T cells, but induces the maintenance of these cells in a quiescent precursor state. They further point to a tissue specificity of this hyporesponsiveness, suggesting that not all donor alloantigen-reactive cells are subject to this regulation.