We previously showed that the cell surface-expressed Mr 70,000 heat shock cognate (hsc70, a constitutively expressed member of the hsp70 family) protein-like molecule (#067 molecule) interacts with rat CD3+, CD4-, CD8-, T-cell receptor (TCR)alphabeta-, natural killer recetor-P1- T cells. This 70hsc-like molecule was also suggested to present cellular peptide antigens to these T cells. In the present study, we identified the genetic structure of the TCR by establishing T-cell hybridomas between these T cells and mouse BW5147 cells. Our data indicated that these T cells preferentially used TCRs with the Vdelta6 family. Analysis of the nucleotide sequence of the CDR3 junctional portion showed that there are substantial diversities, with insertion of seven to nine amino acid residues. These data provide indirect evidences for our hypothesis that an hsc70-like molecule could be presented together with cellular peptide antigens to particular T cells with TCR gammadelta chains. Since the expression of this hsc70-like #067 antigen on the cell surface is usually induced along with cell transformation by activated oncogenes, T cells with the TCR Vdelta6 family are likely to contribute to host resistance to tumor cells.
Abstract:We previously reported that rat T-cell receptor (TCR) V␦6 of T-cell hybridomas was preferentially involved in recognition of the cell surface-expressed 70 kDa rat heat-shock cognate (hsc70, a constitutively expressed member of the hsp 70 family) protein-like molecule (#067 molecule). In the present study, we analyzed usage of the TCR V␥ family of #067-restricted T-cell hybridomas. Our data indicated that most of these hybridomas expressed transcripts of TCR V␥1 and/or V␥2. However, some of the V␥2 transcripts were out-of-frame, suggesting that the TCR V␥1 family may be important for the recognition of #067-defined molecules. TCR V␥1 transcripts were detected in not only #067-restricted T-cell hybridomas, but #067-non restricted ones as well. However, V-J nucleotide sequences of #067-restricted and #067-non restricted T-cell hybridomas suggested that #067-restricted T-cell hybridomas showed limited insertion of nucleotide stretch as compared with #067-non restricted ones. In terms of amino acids, only one amino acid was added in #067-restricted T-cell hybridomas, whereas two or three amino acids were added in #067-non restricted ones. These data suggest that the heterodimer of the TCR relatively short stretch form of V␥1 molecule and TCR V␦6 may participate in recognition of the #067 molecule. Key words: Rat hsc70-like molecule, T-cell hybridomas, TCR V␥ usage 351Microbiol. Immunol., 47(5), [351][352][353][354][355][356][357] 2003 Abbreviations: DNT, CD4(−) and CD8(−) double-negative T cells; hsc70, 70 kDa heat-shock cognate protein; hsp, heat-shock protein; hsp70, 70 kDa heat-shock protein; RT-PCR, reverse transcription-polymerase chain reaction.
Pulmonary veno-occlusive disease (PVOD) is an extremely rare condition in oncology practice. Although PVOD is clinically similar to pulmonary arterial hypertension, the conditions differ in terms of pathophysiology, management, and prognosis. This report discusses the case of a 47-year-old woman who developed dyspnea and fatigue after high-dose cyclophosphamide chemotherapy and autologous hematopoietic stem cell transplantation for relapsed lymphoma. The patient exhibited tachycardia, tachypnea, and hypotension, but other findings in the physical examination were unremarkable. The imaging studies showed no evidence of pulmonary embolism, but multiple ground-glass opacities and bilateral pleural effusions were observed on chest high-resolution computed tomography scans. In the right heart catheterization study, the mean pulmonary artery pressure and pulmonary vascular resistance were 35 mm Hg and 5.93 Wood units, respectively, with a normal pulmonary capillary wedge pressure of 10 mm Hg. Pulmonary function tests revealed a remarkable reduction in the percentage predicted value of diffusing capacity of the lungs for carbon monoxide to 31%. Lymphoma progression, collagen diseases, infectious diseases such as human immunodeficiency virus or parasitic infections, portal hypertension, and congenital heart disease were carefully excluded as these are also capable of causing pulmonary arterial hypertension. Thereafter, we reached a final diagnosis of PVOD. The patient was treated with supplemental oxygen and a diuretic during 1 month of hospitalization, which relieved her right heart overload symptoms. Herein, we present the patient’s clinical course and diagnostic workup because misdiagnosis or inappropriate treatment can lead to unfavorable outcomes in patients with PVOD.
Background: Cytokine induced killer cells (CIK) are an advanced therapeutic medicinal product (ATMP) composed of activated, mostly CD8 + , T cells with anti-tumor but little graft versus host disease (GvHD) activity, even in an allogeneic setting. In our recent phase II clinical trial, 73 leukemia/lymphoma patients, relapsed after allogeneic hematopoietic stem cell transplantation, were treated with a low dose of donor lymphocyte infusion (DLI) followed by 3 infusions of donor-derived CIK cells. The results suggested that CIK have therapeutic activity against low burden disease and confirmed their limited GvHD potential. Aims: In order to increase the specificity and efficacy of CIK, we have investigated the possibility of combining them with CD3xCD19 bispecific T cell engager (BiTE) antibody blinatumomab to better control CD19 + tumors. Methods: CIK cells were expanded in vitro from peripheral blood (PB) or cord blood (CB) mononuclear cells by stimulation with interferon-gamma (IFN-g), anti-CD3 antibody and recombinant interleukin-2 (rhIL-2). They were tested in vitro and in vivo for their capacity to degranulate (CD107a induction), proliferate (cell count, 7-AAD staining, CSFE assays) and induce killing of CD19 targets in presence or absence of blinatumomab (calcein-AM release assays). The efficacy of CIK and blinatumomab was also tested in vivo in a mouse model of acute lymphoblastic leukemia (ALL-2, patient-derived model). Results:We show that CIK cells can be efficiently redirected against leukemic targets in presence of blinatumomab, both in vitro and in vivo. Target cells were killed in vitro up to 40-80% in presence of blinatumomab at 1:1 and 1:10 effector target ratios, respectively, compared to 2-33% in the absence of blinatumomab. More detailed analysis of cell cultures showed that, in vitro, CIK degranulate at 2-4 hours, and in part die at 48 hours but then very rapidly proliferate at days 4-7 following exposure to CD19 + targets, blinatumomab and rhIL-2. In vivo in mice CIK had significantly enhanced therapeutic activity in presence compared to absence of blinatumomab (mean survival time of 62 days compared to 46 days, p < 0.01). Also human CIK could still be detected in the bone marrow and spleen of animals up to 4 weeks after infusion. Summary/Conclusion: Our data are summarized in Fig. 1 and suggest that blinatumomab has the strong capacity to signal CIK to proliferate and become cytotoxic against CD19 + tumor targets, both in vitro and in vivo. This is reminiscent of what is observed using CAR19-modified T cells. We suggest that CIK, combined with blinatumomab, offer a novel and effective immunotherapy approach for the treatment of CD19 + tumors. This approach is flexible, allowing to taper the BsAb in case of toxicity and, in the future, to use different T cell engaging antibodies for blinatumomab-refractory, CD19 negative tumors (Fig. 1). We propose to perform a Phase I clinical trial to test the safety of the combination of in vitro expanded T cells and blinatumomab.
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