Upon transplantation of T cells from a CD28 superagonist (CD28-SAKeywords: aGvHD r Conventional T cells r CD28 superagonist r GvT effect Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAcute graft versus host disease (aGvHD) still constitutes a major obstacle to successful treatment of hematological malignancies by the transplantation of allogeneic T cells [1]. It is the allogeneic T cells themselves that mediate the beneficial graft versus tumor (GvT) effect and induce the potentially life-threatening aGvHD [2]. Therefore, it has been a long-standing aim to establish protocols that prevent aGvHD while not abrogating the GvT effect [1][2][3]. In this respect, the use of CD4 + CD25 + Foxp3 + regulatory T cells (T reg cells) has proven very promising in that they have, indeed, been shown to suppress aGvHD [4][5][6][7][8][9], but not the GvT effect in experimental animal models [4][5][6][7][8][9][10]. In the human system, T reg cell numbers are very low in the peripheral blood to Correspondence: Dr. Niklas Beyersdorf e-mail: niklas.beyersdorf@vim.uni-wuerzburg.de begin with and it may, thus, well be that demanding protocols for large-scale amplification of still functional T reg cells in vitro prior to transplantation in vivo might have to be implicated to robustly achieve prevention of aGvHD in humans [11][12][13]. An alternative to the transplantation of T reg cells for aGvHD prevention is to manipulate, also in the human system amply available, conventional CD4 + T cells (CD4 + T conv cells). Published work indicates that effector memory-phenotype T cells [14][15][16][17][18] and in vitro preactivated CD4 + T cells induce less aGvHD in allogeneic recipients than resting CD4 + T cells [8,[19][20][21][22]. However, at least for some of these settings, including the stimulation of total CD4 + T cells with a superagonistic anti-CD28 monoclonal antibody (CD28-SA) in vitro, it has been shown that it is the preferential expansion of T reg cells over CD4 + T conv cells, which underlies the reduced induction of aGvHD [8,23]. Therefore, we determined whether polyclonal stimulation of T conv cells would be sufficient for protection from aGvHD while, ideally, maintaining the GvT effect. To this end we compared two protocols: one Eur. J. Immunol. 2015. 45: 1997 employing CD28-SA-coated beads and the other anti-CD3/anti-CD28 mAb-coated beads. One reason for immobilizing the CD28-SA on beads was to be able to separate the CD28-SA from the T cells so that only T cells, but not the CD28-SA is infused into the allogeneic host. This appeared to be an essential component of our protocol at the time we designed these experiments as a CD28-SA had elicited a cytokine storm during phase I clinical testing in healthy volunteers in vivo [24]. Very recent data from another phase I study, however, clearly show that low dosages of CD28-SA do not induce a cytokine storm in humans but lead to an IL-10-dominated immunoregulatory response [25]. This means that rigorou...
Peripheral T cell lymphomas (PTCLs) are associated with a poor prognosis due to often advanced disease at the time of diagnosis and due to a lack of efficient therapeutic options. Therefore, appropriate animal models of PTCL are vital to improve clinical management of this disease. Here, we describe a monoclonal CD8+ CD4− αβ T cell receptor Vβ2+ CD28+ T cell lymphoma line, termed T8-28. T8-28 cells were isolated from an un-manipulated adult BALB/c mouse housed under standard pathogen-free conditions. T8-28 cells induced terminal malignancy upon adoptive transfer into syngeneic BALB/c mice. Despite intracellular expression of the cytotoxic T cell differentiation marker granzyme B, T8-28 cells appeared to be defective with respect to cytotoxic activity as read-out in vitro. Among the protocols tested, only addition of interleukin 2 in vitro could partially compensate for the in vivo micro-milieu in promoting growth of the T8-28 lymphoma cells.
IntroductionFor many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication.MethodsTherefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD.ResultsTreatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4+ T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4+ and CD8+ T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4+ T cells with a relative resistance of CD4+ regulatory and CD8+ T cells toward Hsp90 inhibition.ConclusionsOur data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect.
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