Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B- cell non-Hodgkin lymphoma

Hertenstein, Bernd; Wagner, Bettina; Bunjes, Donald; Duncker, Christian; Raghavachar, Aruna; Arnold, Renate; Heimpel, Hermann; Schrezenmeier, Hubert

doi:10.1182/blood.v86.4.1487.bloodjournal8641487

Cited by 92 publications

(31 citation statements)

References 25 publications

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“…Of interest, in the clinical course of the patient with AA ( Fig 4A), erythrocytes (and granulocytes) that were negative for both DAF and CD59 (a PNH phenotype), which are known as reliable indicators of a favourable response to IST in AA (Sugimori et al, 2006), were detectable by our flow cytometry 5 months after the first appearance of NKG2D ligand-expressing granulocytes in 2004 (data not shown). Concerning this latency in detection of PNH-type cells of the patient, it is conceivable that flow cytometric detection needs a period of time for accumulation of PNH-type cells by immunoselection which probably begins with the appearance of NKG2D ligands (Bessler et al, 1994;Hertenstein et al, 1995;Young, 2000;Murakami et al, 2002;Nagakura et al, 2002;Inoue et al, 2003;Nakakuma & Kawaguchi, 2003;Hanaoka et al, 2006;Kawaguchi & Nakakuma, 2007). It is also suggested that detection of PNH clones is occasionally difficult when PNH clones coexist with other expanding clones, like leukaemic cells (Kawano et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

NKG2D‐mediated immunity underlying paroxysmal nocturnal haemoglobinuria and related bone marrow failure syndromes

et al. 2009

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It is considered that a similar immune mechanism acts in the pathogenesis of bone marrow (BM) failure in paroxysmal nocturnal haemoglobinuria (PNH) and its related disorders, such as aplastic anaemia (AA) and myelodysplastic syndromes (MDS). However, the molecular events in immune-mediated marrow injury have not been elucidated. We recently reported an abnormal expression of stress-inducible NKG2D (natural-killer group 2, member D) ligands, such as ULBP (UL16-binding protein) and MICA/B (major histocompatibility complex class I chain-related molecules A/B), on granulocytes in some PNH patients and the granulocyte killing by autologous lymphocytes in vitro. The present study found that the expression of NKG2D ligands was common to both granulocytes and BM cells of patients with PNH, AA, and MDS, indicating their exposure to some incitement to induce the ligands. The haematopoietic colony formation in vitro by the patients' marrow cells significantly improved when their BM cells were pretreated with antibodies against NKG2D receptor, suggesting that the antibodies rescued haematopoietic cells expressing NKG2D ligands from damage by autologous lymphocytes with NKG2D. Clinical courses of patients with PNH and AA showed a close association of the expression of NKG2D ligands with BM failure and a favourable response to immunosuppressive therapy. We therefore propose that NKG2D-mediated immunity may underlie the BM failure in PNH and its-related marrow diseases.

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Section: Discussionmentioning

confidence: 99%

NKG2D‐mediated immunity underlying paroxysmal nocturnal haemoglobinuria and related bone marrow failure syndromes

et al. 2009

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“…The second part of the hypothesis has proven much more refractory. Indirect evidence has continued to accumulate; for instance, the demonstration by Araten et al (1999) that PIG-A mutations are present at exceedingly low levels in normal individuals, and the discovery that such mutant clones can temporarily expand during iatrogenic selection with CAMPATH antibodies (against the GPI-linked antigen CD52) during therapy of lymphomas (Hertenstein et al, 1995). However, the mechanism selecting for the expansion of mutant clones in spontaneous PNH has remained obscure.…”

Section: Discussionmentioning

confidence: 99%

Differential apoptosis and Fas expression on GPI‐negative and GPI‐positive stem cells: a mechanism for the evolution of paroxysmal nocturnal haemoglobinuria*

Ismail¹,

Tooze²,

Flynn³

et al. 2003

Br J Haematol

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Summary. Paroxysmal nocturnal haemoglobinuria (PNH) has a dual pathogenesis. PIG-A mutations generate clones of haemopoietic stem cells (HSC) lacking glycosylphosphatidylinositol (GPI)-anchored proteins and, secondly, these clones expand because of a selective advantage related to bone marrow failure. The first aspect has been elucidated in detail, but the mechanisms leading to clonal expansion are not well understood. We have previously shown that apoptosis and Fas expression in HSC play a role in bone marrow failure during aplastic anaemia. We have now investigated apoptosis in PNH. Ten patients were studied. Apoptosis, measured by flow cytometry, was significantly higher among CD34 + cells from patients compared with healthy controls. Fas expression was also increased. Cells that were stained for CD34, CD59 and apoptosis showed a significantly lower apoptosis in CD34 + /CD59 ) compared with CD34 + /CD59 + cells from the same patient. In three patients, staining for CD34, CD59 and Fas revealed lower Fas expression on CD34 + /CD59 ) cells. Differential apoptosis of CD34 + /CD59 ) HSC may be sufficient in itself to explain the expansion of PNH clones in the context of aplastic anaemia. In addition to demonstrating a basic mechanism underlying PNH clonal expansion, these results suggest further hypotheses for the evolution of PNH, based on the direct or indirect resistance of GPI-negative HSC to pro-inflammatory cytokines.

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“…Paroxysmal nocturnal haemoglobinuria (PNH) is a chronic disorder characterized by episodes of intravascular haemolysis often associated with abdominal pain, recurrent lifethreatening venous thrombosis and an intimate association with aplastic anaemia (AA) (Hillmen et al, 1995;Socie et al, 1996). PNH is a clonal disorder arising due to a somatic mutation in a pluripotent haemopoietic stem cell.…”

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confidence: 99%

“…A signi®cant proportion (up to 52%) of patients with AA will eventually develop a PNH clone . In addition the majority of patients with PNH have signi®cant cytopenias at some stage in their illness (Hillmen et al, 1995). Considering that both AA and PNH are rare disorders this association cannot be a chance ®nding.…”

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confidence: 99%

The PNH phenotype cells that emerge in most patients after CAMPATH‐1H therapy are present prior to treatment

et al. 1999

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Paroxysmal nocturnal haemoglobinuria (PNH) cells are deficient in glycosylphosphatidylinositol (GPI) linked antigens due to a somatic mutation of the PIG-A gene in a haemopoietic stem cell. It appears that a PNH clone reaches detectable proportions only when there is selection in its favour. GPI-deficient T lymphocytes have been identified in patients treated with CAMPATH-1H, a monoclonal antibody against the GPI-linked CD52 molecule. CAMPATH-1H selects for cells that are deficient in CD52 (such as PNH-like cells) promoting the development of a PNH-like clone (analogous to PNH). We report that 10/15 patients with chronic lymphocytic leukaemia developed PNH-like lymphocytes after therapy with CAMPATH-1H. The remaining five patients developed no PNH-like cells at any stage, including one patient who received 12 weeks of therapy. The inactivating PIG-A mutation has been identified in one patient. This mutation was detectable by an extremely sensitive mutation-specific PCR-based analysis in the patient's mononuclear cells prior to CAMPATH-1H therapy. The frequency and phenotype of GPI-deficient lymphocytes after CAMPATH-1H and the detection of a PIG-A mutation in the lymphocytes prior to CAMPATH-1H therapy indicated that such mutations were present in a very small proportion of cells prior to selection in their favour by CAMPATH-1H. This suggests that a large proportion of individuals have cells with PIG-A mutations that are not detectable by flow cytometry and thus may have the potential to develop PNH.

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Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B- cell non-Hodgkin lymphoma

Cited by 92 publications

References 25 publications

NKG2D‐mediated immunity underlying paroxysmal nocturnal haemoglobinuria and related bone marrow failure syndromes

NKG2D‐mediated immunity underlying paroxysmal nocturnal haemoglobinuria and related bone marrow failure syndromes

Differential apoptosis and Fas expression on GPI‐negative and GPI‐positive stem cells: a mechanism for the evolution of paroxysmal nocturnal haemoglobinuria*

The PNH phenotype cells that emerge in most patients after CAMPATH‐1H therapy are present prior to treatment

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