Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide

Abstract

Regulatory T cells (T REGs ) control the key aspects of tolerance and play a role in the lack of antitumor immune responses. Cyclophosphamide (CY) is a chemotherapeutic agent with a dose-dependent, bimodal effect on the immune system. Although a previous study demonstrated that CY reduces the number of T REGs , the mechanism involved in this process has yet to be defined. In this report, it is established that low-dose CY not only decreases cell number but leads to decreased functionality of T REGs . CY treatment enhances apoptosis and decreases homeostatic proliferation of these cells. Expression of GITR and FoxP3, which are involved in the suppressive activity of T REGs , is down-regulated after CY administration, though the level of expression varies depending on the time studied. This is the first report demonstrating that CY, in addition to decreasing cell number, inhibits the suppressive capability of T REGs . The relevance of the loss of suppressor functionality and the changes in gene expression are further discussed.

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

“…In a subsequent experiment IL2-cas was given 3 days after administration of Cy, the time point of maximal lymphodepletion [4,5,29]. Administration of 1-4 doses of 1 μg/g IL2-cas after 200 μg/g Cy to prediabetic female NOD mice decreased the incidence of hyperglycaemia in all age groups (Fig.…”

“…Impact of cyclophosphamide and IL2-cas on diabetes in NOD mice In view of the evidence that IL2-cas induces apoptosis in CD25 + T cells and decreases effector activity, the fusion protein was evaluated in NOD mice in vivo. On the one hand, an agent that mediates targeted killing of CD25 + T cells is expected to precipitate early onset of diabetes similar to cyclophosphamide [4][5][6] and anti-CD25 antibodies [27,28]. On the other hand, decreased activity of reactive cells suggests that the fusion protein might ameliorate the course of insulitis as observed with diphtheria toxin in NOD mice [20] and IL2-cas in inflammatory colitis [22,23,25].…”

“…Immunological consequences of immunomodulation To determine the acute-phase consequences of administration of the two agents, lymphoid organs were evaluated at the nadir of lymphopenia caused by Cy in NOD mice [4,5,29]. Female NOD mice aged 8 weeks received one intraperitoneal dose of 200 μg/g Cy or 4 μg/g IL2-cas and after 3 days the spleens, mesenteric/pancreatic lymph nodes and thymus were compared with age-and sexmatched naive NOD mice (Fig.…”

“…Administration of one dose of cyclophosphamide (Cy) has been long recognised to induce diabetes in NOD mice. While causing transient lymphodepletion [4,5], this agent is particularly toxic to naturally occurring Treg that express cluster of differentiation (CD) 25 and Forkhead box P3 (FOXP3), causing both their depletion and functional inactivation in the pancreas and its draining lymph nodes [4]. Subsequent administration of agents that stimulate immuno-haematopoietic reconstitution partially reverse the toxic effects of Cy by increasing the pool of suppressor cells [6], as does adoptive transfer of Treg [4].…”

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…36 Most platinum-based compounds inhibit STAT6-regulated expression of programmed death ligand-2, thus limiting immunosuppression by both DCs and tumor cells. 74 Low-dose CTX selectively, but transiently, suppresses Tregs 43,75,76 and impairs the production of immune-suppressive cytokines, such as IL-4, IL-10 and IL-13. 41,77 A prolonged and more effective Treg inhibition was achieved by metronomic CTX regimens in patients with advanced solid tumors 6 or with metastatic breast cancer.…”