Aging strongly promotes inflammation responses, which may predispose individuals after cancer therapies to lethal system toxicities and pathology that can be partially prevented by TNF blockade.

We have recently demonstrated that the proteasome inhibitor, bortezomib, administered immediately following murine allogeneic bone marrow transplantation (BMT) resulted in marked inhibition of acute graft-versus-host disease (GVHD) with retention of graft-versus-tumor effects. We now assessed the effects of delayed bortezomib administration (5 or more days after BMT) on GVHD. Recipient C57BL/6 (H2 b ) mice were lethally irradiated and given transplants of bone marrow cells and splenocytes from major histocompatibility complex (MHC)-disparate BALB/c (H2 d ) donors. In marked contrast to the effects of bortezomib on GVHD prevention when administered immediately after BMT, delayed bortezomib administration resulted in significant acceleration of GVHD-dependent morbidity. No toxicity was observed following delayed bortezomib administration in models where donor T cells were not coadministered, indicating that these deleterious effects were critically dependent on GVHD induction. The increase in GVHD susceptibility even occurred when late administration of bortezomib was preceded by early administration. Pathologic assessment revealed that significant increases in gastrointestinal lesions occurred following delayed bortezomib administration during GVHD. This pathology correlated with significant increases of type 1 tumor necrosis factor ␣ (TNF- ␣ IntroductionThe occurrence of acute graft-versus-host disease (GVHD) remains one of the most significant causes of morbidity following allogeneic bone marrow transplantation (BMT). GVHD is caused by administration of donor T cells into a genetically disparate recipient. The pathophysiology of GVHD is a complex process that can be conceptualized in 3 phases. [1][2][3] In the first phase, the cytoreductive conditioning regimen causes immunosuppression of the recipients and damage to host tissues, including a self-limited burst of inflammatory cytokines. In the second phase, donor T cells recognize alloantigens on host antigen-presenting cells (APCs) and these activated T cells then proliferate and differentiate into effector cells. The second phase is critical for the amplification of the systemic inflammatory response, in which donor T cells also contribute to the inflammatory cytokine network. In the third phase, target tissues undergo apoptosis mediated by cellular effectors and inflammatory cytokines such as tumor necrosis factor ␣ (TNF-␣) and interferon ␥, and further host tissue injury establishes a positive inflammatory feedback loop. Solid organs attacked during acute GVHD include the gut, liver, lungs, and skin. [1][2][3] The proteasome is a multicatalytic proteinase complex responsible for the degradation of most intracellular proteins, including proteins crucial to cell-cycle regulation and apoptosis. Bortezomib (Velcade, formerly PS-341) is the first of its class of proteasome inhibitors to be tested in humans and has shown promising activity in several tumor types, especially in hematologic malignancies. 4 It has recently been approved as a therapy in multiple mye...

Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naive, CD8 ؉ T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through T-cell receptors (TCRs) or CD3 in both mouse and human memory CD8 ؉ T cells markedly up-regulated programmed death-1 (PD-1) and CD25 (IL-2 receptor ␣ chain), and led IntroductionMemory T cells represent an arm of the adaptive immune system that are long-lived, and capable of rapid antigen-specific responses. Memory T cells have been shown to have functional advantages more than naive T cells, as they develop more rapidly into cytolytic effector cells and produce greater amounts of cytokines after antigenic stimulation. 1 Although T cells classically require T-cell receptor (TCR) engagement and proper costimulation for complete activation and proliferation, memory T cells have also been observed to proliferate in response to various cytokines during viral infections. [2][3][4][5][6] These "bystander cells" proliferate and gain effector functions in response to the cytokine milieu produced during the course of viral and bacterial infections in mice and humans. [7][8][9][10] Cytokines alone can induce this as a single dose of recombinant type-I interferon (IFN) resulting in a transient increase in the proliferation of CD8 ϩ , CD62L ϩ CD44 high memory T cells, which was independent of coligation of the TCRs. 11 Such proliferation was not induced by the direct effects of type-I IFNs on CD8 ϩ T cells, but was because of type-I IFN-driven production of secondary cytokines such as 12 Effector and memory CD8 ϩ T cells express elevated levels of the receptors for IL-12 and IL-18, and secrete IFN-␥ in response to stimulation with both cytokines, 13 which suggests that other cytokine pathways can also induce their expansion. Similar to the secondary cytokine-driven proliferation observed after type-I IFN stimulation, IL-2, and toll-like receptor (TLR) agonists, that is, CpG and Poly:IC have also been described as having the capacity to induce bystander proliferation of CD8 ϩ CD44 high T cells. 12,14,15 The extent of antigen-specific proliferation versus bystander expansion has been the subject of considerable debate and may be contingent on the pathogen model and tissue examined. 9,13,16 Cancer therapies that target the stimulation of the immune system via agonist antibodies, cytokine-based modalities, or TLR agonists have been shown to result in potent CD8 ϩ T cell-mediated antitumor effects. 17,18 We have previously shown that a combination immunotherapy consisting of an agonist CD40 antibody and IL-2 results in synergistic antitumor effects. 19 Treatment of mice with other cytokine or TLR agonist combinations, such as CpGs and IL-15 or IL-2 and IL-12, also resulted in marked antitumor effects. 18 In all of these models, the antitumor effects were associated with rapid, extensive CD8 ϩ T-cell expansion. The antitumor effec...