Expression of T cell activation antigen CD134 (OX40) has no predictive value for the occurrence or response to therapy of acute graft-versus-host disease in partial T cell-depleted bone marrow transplantation

Abstract

Summary:CD134 (OX40) is a member of the tumor necrosis factor family which is expressed by activated T lymphocytes. CD134 expression on T cells was monitored during the first 35 days post-transplant in 14 patients, receiving either an HLA-identical sibling bone marrow transplant (BMT), a matched unrelated transplant (MUD-BMT) or an autologous peripheral blood progenitor cell transplant (PBPCT). The sibling and unrelated grafts were partially depleted of T cells. CD134 expression on CD4 + T cells peaked between 7 and 14 days after BMT, with a mean peak value of 45% of CD4 + cells (range 26-70%) over all three patient groups. The observed pattern of CD4 + CD134 + expression, an increase during the first 2 weeks post-BMT followed by a gradual decline towards values of 15-40%, was similar in all groups. No difference in the kinetics of CD134 expression by CD4 + T cells was observed between the patients that did or did not develop graft-versus-host disease (GVHD), nor did the clinical effect of any treatment given for GVHD correlate with alterations in CD134 expression by CD4 + T cells. Absolute CD4 + ,CD134 + T cell numbers showed a more rapid increment after autologous PBPCT than after sibling or MUD transplants. We conclude that expression of CD134 + by CD4 + T lymphocytes cannot serve as a surrogate marker for allo-reactivity. CD134 + expression may reflect lymphocyte regeneration, rather than alloreactivity. Keywords: graft-versus-host disease; T cell; CD134 antigen; bone marrow transplantation; reconstitution Graft-versus-host disease (GVHD) is still a major and potentially lethal complication of allogeneic bone marrow transplantation (BMT). 1 It has been shown that GVHD is initiated by donor-derived, alloreactive cytotoxic T lymphocytes (CTLs, CD8 + ) and helper T lymphocytes (CD4 + ), which is then further amplified by elaboration of cytokines. 2,3 The 'cytokine storm' concept of GVHD is defined as an outpouring of endogenous cytokines resulting in an attack of various tissues by antigen-specific and non-specific effector leukocyte populations. 3,4 Acute GVHD is preferably diagnosed on the basis of clinical signs together with biochemical data (liver enzymes, bilirubin). 5 Other ways of monitoring and predicting acute GVHD have been proposed, such as the repopulation pattern of the T lymphocytes. 6 The rate of CD8 + T cell repopulation and the expression of T cell activation markers such as CD25 have been shown to predict GVHD in some patient cohorts. 7,8 CD134 (OX40) is a 50-kDa type I transmembrane protein that is expressed on activated CD4 + T lymphocytes and to a lesser extent on CD8 + T lymphocytes. 9 It is a member of the tumor necrosis factor (TNF)/nerve growth factor (NGF) family. CD134 is rarely expressed by lymphocytes under normal conditions and, if it is, mainly by T lymphocytes residing in the lymph nodes. The ligand (L) for CD134 is a gp34 membrane bound protein, structurally similar to other ligands in the TNF receptor family with a still incompletely documented tissue distribution (activated B...

Correlation of peripheral blood OX40+(CD134+) T cells with chronic graft-versus-host disease in patients who underwent allogeneic hematopoietic stem cell transplantation

“…In contrast, previous studies showed that monitoring OX40 ϩ T cells was not useful for the prediction of aGVHD. 17 We assume that the pathogenesis of aGVHD and cGVHD may not be identical 2 and infections that are more common within 100 days after allo-HSCT 18 might modify the expression of OX40.…”

Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients

“…Several but not all studies in humans have suggested that OX40 up-regulation can precede acute GVHD generation and may be a marker of steroid-resistant acute GVHD or chronic GVHD. [44][45][46][47] Regardless of whether the upregulation of OX40 receptor is of prognostic significance, interruption of the OX40/OX40L pathway early in the post-BMT period warrants testing as an approach to prevent GVHD and allogeneic BM graft rejection.…”

Normal IgG protects against acute graft-versus-host disease by targeting CD4+CD134+ donor alloreactive T cells

“…Such a mechanism for the protective effect of IVIg is of particular interest since, in a similar parent into F1 animals model of aGVHD, the presence of CD4 + CD134 + T cells was suggested to be associated with the onset and clinical course of aGVHD [23]. Furthermore, CD4 + CD134 + T cells recovered from methylprednisolone-treated patients with GVHD were documented as being resistant to apoptosis [24].…”