Intravenous Monoclonal Antibody (BT 5/9) for the Treatment of Acute Graft-versus-Host Disease

Bacigalupo, Andrea; Corte, Giorgio; Ramarli, Dunia; Lint, Van; Frassoni, Francesco; Marmont, A

doi:10.1159/000206319

Cited by 14 publications

(5 citation statements)

References 5 publications

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“…In view of these findings, CD26 can potentially be a target for immunotherapy. In fact, anti‐CD26 treatment was reported to be effective in decreasing the incidence of steroid‐resistant acute GVHD after allogeneic bone marrow transplantation 44,45 although the precise mechanism involved in these clinical results is not yet elucidated. Our data therefore suggest that cell cycle regulation of activated T cells via CD26 might be useful for controlling acute GVHD by inhibiting cellular proliferation.…”

Section: Discussionmentioning

confidence: 99%

G1/S cell cycle arrest provoked in human T cells by antibody to CD26

et al. 2002

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SUMMARYCD26 is T cell costimulatory molecule with dipeptidyl peptidase IV (DPPIV) enzyme activity located in its extracellular region. The expression of CD26 is enhanced after activation of T cells, while it is preferentially expressed on a subset of CD4 þ memory T cells in the resting state. In this paper, we demonstrate that binding of the soluble anti-CD26 monoclonal antibody (mAb) 1F7 inhibits human T-cell growth and proliferation in both CD26-transfected Jurkat T-cell lines and human T-cell clones by inducing G1/S arrest, which is associated with enhancement of p21 Cip1 expression. This effect depends on the DPPIVenzyme activity of the CD26 molecule. Moreover, we show that expression of p21 Cip1 after treatment with the anti-CD26 mAb 1F7 appears to be induced through activation of extracellular signal-regulated kinase (ERK) pathway. These data thus suggest that anti-CD26 treatment may have potential use in the clinical setting involving activated T cell dysregulation, including autoimmune disorders and graft-vs.-host disease. INTRODUCTIONCD26 is a 110 000 MW cell-surface glycoprotein that possesses dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) activity in its extracellular domain, and plays an important role in T-cell activation. 1,2 Recently identified as the adenosine deaminase (ADA) binding protein, CD26 regulates ADA surface expression, with the CD26/ADA complex perhaps playing a key role in the catalytic removal of local adenosine to regulate immune function. 3 Although constitutively expressed in the liver, intestine and kidney, CD26 expression level is tightly regulated on T cells, and its density is markedly enhanced after T cell activation. 1,4 In the resting state of T cells, CD26 is expressed on a subset of CD4 þ memory T cells, and this CD4 þ CD26 high T-cell population has been shown to respond maximally to recall antigens. 1,5 In fact, CD26 itself is involved in the signal transduction process of T cells. 1 Cross-linking of CD26 and CD3 with immobilized monoclonal antibodies (mAbs) can induce T-cell activation and interleukin (IL)-2 production. 1,2,6 Moreover, anti-CD26 antibody treatment of T cells leads to a decrease in the surface expression of CD26 via its internalization, and this modulation of CD26 on T cells results in an enhanced proliferative response to anti-CD3 or anti-CD2 stimulation. 7 While ligation of the CD26 molecule by the anti-CD26 mAb 1F7 induces increased tyrosine phosphorylation of signalling molecules such as CD3-zeta, extracellular signalregulated kinase (ERK), p56 lck , and ZAP-70 8,9 we showed previously that the anti-CD26 mAb 1F7 inhibits tetanus-toxoid induced T-cell proliferation. 10 In normal T cells, engagement of CD26 results in increased phosphorylation of proteins involved in T-cell signal transduction, mediated in part through the physical association of CD26 and CD45 in lipid rafts. 11 Besides being a key immunoregulatory molecule, CD26 may have a potential role in the development of certain neoplasms, including aggressive T-cell haematological malignancies. ...

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Section: Discussionmentioning

confidence: 99%

G1/S cell cycle arrest provoked in human T cells by antibody to CD26

et al. 2002

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“…Although treatment with a murine antibody against human CD26 exerted the therapeutic effect of controlling GVHD in patients with steroid-resistant acute GVHD following alloHSCT (Bacigalupo et al, 1985;de Meester et al, 1993), the precise cellular basis of human GVHD, as well as the role of CD26 in this process, has not yet been clearly delineated. To address this issue, we examined human GVHD tissue biopsies in alloHSCT recipients with or without active GVHD.…”

Section: Cd26 + Mncs Infiltrate the Skin Or Gi Tract Of Allohsct Patimentioning

confidence: 99%

Prevention of acute graft‐versus‐host disease by humanized anti‐CD26 monoclonal antibody

et al. 2013

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SummaryCD26 (DPP4) is a T cell costimulatory molecule as well as T cell activation marker, and CD26 + T cells are accumulated in inflamed tissues, such as rheumatoid synovitis and autoimmune thyroiditis. In the present study, we found accumulation of CD26 + T cells in graft-versus-host disease (GVHD) target organs. To expand our in vitro findings to an in vivo system, we examined CD26-dependent organ injury in a xenogeneic GVHD (x-GVHD) murine model. Following intraperitoneal injection of human peripheral blood mononuclear cells into non-obese diabetic severe combined immunodeficiency/c c À/À mice (hu-PBL-NOG mice), the mice exhibited the onset of GVHD symptoms associated with the presence of CD26 high human lymphocytes in the peripheral blood and GVHD target tissues. Administration of humanized anti-human CD26 monoclonal antibody (mAb) decreased x-GVHD severity and prolonged survival in hu-PBL-NOG mice without loss of engraftment of human T cells, while increasing doses of CTLA4-immunoglobulin fusion protein diminished engraftment of human lymphocytes. Importantly, anti-CD26 mAb treatment preserved the graftversus-leukaemia effects in studies using cotransplantation of P815 murine leukaemic cells. In addition, CD26 + lymphocytes infiltrated the GVHD patients' target tissues. Altogether, our data indicate a role for CD26 in the regulation of GVHD and point to CD26 as a novel target for therapeutic intervention in this disease.

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“…Some approaches (e.g., B7-blocking, OX40-blocking, and T-cell depletion by specific antibodies) to promote the positive effects of alloSCT without GVHD have been developed recently in the clinical settings (reviewed in (106)). Although the role of CD26/DPPIV in GVHD needs to be studied in more detail, treatment with a murine antibody against human CD26 was reported to have an effect in patients with steroid-resistant acute GVHD following alloSCT (107,108).…”

Section: Graft-versus-host Disease (Gvhd)mentioning

confidence: 99%

Role of CD26/dipeptidyl peptidase IV in human T cell activation and function

Ohnuma

Takahashi²,

Yamochi³

et al. 2008

Front Biosci

119

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CD26 is a 110 kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV, EC 3.4.14.5) activity that is expressed on numerous cell types and has a multitude of biological functions. CD26 role in immune regulation has been extensively characterized, with recent findings elucidating its linkage with signaling pathways and structures involved in T-lymphocyte activation as well as antigen presenting cell (APC)-T-cell interaction. In this paper, we will review emerging data on CD26-mediated T-cell costimulation, suggesting that CD26 may be an appropriate therapeutic target for the treatment of immune disorders. However, the identity of its putative natural ligand had not yet been clearly elucidated. Recently, using protein engineering and proteomic approach, we have recently characterized the putative costimulatory ligand for CD26 in T-cells and the proximal signaling events directly associated with the cytoplasmic region of CD26 in CD26-associated T-cell costimulation, processes that are independent of the CD28 costimulatory pathway. Our work therefore presents novel findings that contribute to the area of T-cell costimulation and signal transduction.

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Intravenous Monoclonal Antibody (BT 5/9) for the Treatment of Acute Graft-versus-Host Disease

Cited by 14 publications

References 5 publications

G1/S cell cycle arrest provoked in human T cells by antibody to CD26

G1/S cell cycle arrest provoked in human T cells by antibody to CD26

Prevention of acute graft‐versus‐host disease by humanized anti‐CD26 monoclonal antibody

Role of CD26/dipeptidyl peptidase IV in human T cell activation and function

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