Different Costimulatory and Growth Factor Requirements for CD4+ and CD8+ T Cell-Mediated Rejection

Self Cite

120

107

Memory T cells can be a significant barrier to the induction of transplant tolerance. However, the molecular pathways that can regulate memory T cell-mediated rejection are poorly defined. In the present study we tested the hypothesis that the novel alternative costimulatory molecules (i.e., ICOS, 4-1BB, OX40, or CD30) may play a critical role in memory T cell activation and memory T cell-mediated rejection. We found that memory T cells, generated by either homeostatic proliferation or donor Ag priming, induced prompt skin allograft rejection regardless of CD28/CD154 blockade. Phenotypic analysis showed that, in contrast to naive T cells, such memory T cells expressed high levels of OX40, 4-1BB, and ICOS on the cell surface. In a skin transplant model in which rejection was mediated by memory T cells, blocking the OX40/OX40 ligand pathway alone did not prolong the skin allograft survival, but blocking OX40 costimulation in combination with CD28/CD154 blockade induced long-term skin allograft survival, and 40% of the recipients accepted their skin allograft for >100 days. In contrast, blocking the ICOS/ICOS ligand and the 4-1BB/4-1BBL pathways alone or combined with CD28/CD154 blockade had no effect in preventing skin allograft rejection. OX40 blockade did not affect the homeostatic proliferation of T cells in vivo, but markedly inhibited the effector functions of memory T cells. Our data demonstrate that memory T cells resisting to CD28/CD154 blockade in transplant rejection are sensitive to OX40 blockade and suggest that OX40 is a key therapeutic target in memory T cell-mediated rejection.

“…The cells were then resuspended in PBS/0.5% BSA for surface staining with specific mAbs (22). After staining, cells were fixed in 1% formaldehyde before analysis by flow cytometry.…”

Section: Flow Cytometrymentioning

confidence: 99%

Section: Monoclonal Abs and Reagentsmentioning

confidence: 99%

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Critical, but Conditional, Role of OX40 in Memory T Cell-Mediated Rejection

Clarkson

Yagita

et al. 2006

Self Cite

120

107

“…Targeting OX40 with an agonist Ab has shown promise in cancer immunotherapy and prevention of infectious diseases (2)(3)(4). In contrast, blocking OX40 signals with an anti-OX40 ligand Ab or an OX40-Ig fusion protein has many potential applications in autoimmune diseases (5)(6)(7)(8).…”

mentioning

confidence: 99%

Activation of NF-κB1 by OX40 Contributes to Antigen-Driven T Cell Expansion and Survival

Song

Croft

2008

109

113

The costimulatory molecule OX40 (CD134) is strongly required in many instances for effective T cell‐mediated immunity, controlling proliferation and survival of T cells after encountering specific antigen. We previously found that the functional targets of OX40 are survivin and aurora B that regulate proliferation, and Bcl‐2 anti‐apoptotic family members that regulate survival. However, the intracellular pathways from OX40 that mediate these effects are unclear. Here, we show that OX40 signaling can target the canonical NF‐kB (NF‐kB1) pathway in peripheral antigen‐responding CD4 T cells. Phosphorylation of IkBalpha which leads to NF‐kB1 (p50)/RelA nuclear translocation is impaired in OX40‐deficient T cells. Retroviral transduction of active IKKbeta that constitutively activates NF‐kB1 rescues the poor proliferation and survival of OX40‐deficient T cells, directly correlating with increased expression and activity of survivin, aurora B, and Bcl‐2 family members. Moreover, active IKKbeta expression alone is sufficient to restore the defective proliferation and survival of OX40‐deficient T cells in vivo when responding to antigen. Thus, OX40 signals regulate T cell number and viability through the NF‐kB1 pathway that controls expression and activity of intracellular targets for proliferation and survival.

“…Everolimus, like rapamycin/sirolimus, interferes with advanced stages of T cell activation by inhibiting growth factor responsiveness (54). Although this might be expected to inhibit both CD4 and CD8 T cells, rapamycin appeared to affect CD8 T cell alloreactivity and proliferation more strongly (55,56). Taken together, it is conceivable that the combinations of anti-CD40L plus anti-LFA-1 and anti-CD40L plus everolimus provide sufficient blockade of both CD4-and CD8-dependent alloreactivity, whereas the combination of anti-LFA-1 plus everolimus may be suboptimal for blocking CD4 T cells.…”

Section: Discussionmentioning

confidence: 99%

Combinations of Anti-LFA-1, Everolimus, Anti-CD40 Ligand, and Allogeneic Bone Marrow Induce Central Transplantation Tolerance through Hemopoietic Chimerism, Including Protection from Chronic Heart Allograft Rejection

Metzler

Gfeller

Bigaud

et al. 2004

Central transplantation tolerance through hemopoietic chimerism initially requires inhibition of allogeneic stem cell or bone marrow (BM) rejection, as previously achieved in murine models by combinations of T cell costimulation blockade. We have evaluated LFA-1 blockade as part of regimens to support mixed hemopoietic chimerism development upon fully allogeneic BALB/c BM transfer to nonirradiated busulfan-treated B6 recipient mice. Combining anti-LFA-1 with anti-CD40 ligand (CD40L) induced high incidences and levels of stable multilineage hemopoietic chimerism comparable to chimerism achieved with anti-CD40L and everolimus (40-O-(2-hydroxyethyl)-rapamycin) under conditions where neither Ab alone was effective. The combination of anti-LFA-1 with everolimus also resulted in high levels of chimerism, albeit with a lower incidence of stability. Inhibition of acute allograft rejection critically depended on chimerism stability, even if maintained at very low levels around 1%, as was the case for some recipients without busulfan conditioning. Chimerism stability correlated with a significant donor BM-dependent loss of host-derived Vβ11+ T cells 3 mo after BM transplantation (Tx). Combinations of anti-CD40L with anti-LFA-1 or everolimus also prevented acute rejection of skin allografts transplanted before established chimerism, albeit not independently of allospecific BMTx. All skin and heart allografts transplanted to stable chimeras 3 and 5 mo after BMTx, respectively, were protected from acute rejection. Moreover, this included prevention of heart allograft vascular intimal thickening (“chronic rejection”).