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Biomedical subjects

R Sackstein

Publications and source records attributed to R Sackstein.

At least 37 records · Page 2Linked to original sources
PubMed1999

The BCR/ABL oncogene alters the chemotactic response to stromal-derived factor-1alpha.

The chemokine stromal-derived factor-1alpha (SDF-1alpha) is a chemoattractant for CD34(+) progenitor cells, in vitro and in vivo. The receptor for SDF-1alpha, CXCR-4, is a 7 transmembrane domain receptor, which is also a coreceptor for human immunodeficiency virus (HIV). Here we show that transformation of hematopoietic cell lines by BCR/ABL significantly impairs their response to SDF-1alpha. Three different hematopoietic cell lines, Ba/F3, 32Dcl3, and Mo7e, were found to express CXCR-4 and to respond to SDF-1alpha with increased migration in a transwell assay. In contrast, after transformation by the BCR/ABL oncogene, the chemotactic response to SDF-1alpha was reduced in all 3 lines. This effect was directly due to BCR/ABL, because Ba/F3 cells, in which the expression of BCR/ABL could be regulated by a tetracycline-inducible promoter, also had reduced chemotaxis to SDF-1alpha when BCR/ABL was induced. The reduced response to SDF-1alpha was not due to an inability of BCR/ABL-transformed cell lines to migrate in general, as spontaneous motility of BCR/ABL-transformed cells was increased. In mice, injection of SDF-1alpha into the spleen resulted in a transient accumulation of untransformed Ba/F3 cells, but not Ba/F3. p210(BCR/ABL) cells administered simultaneously. The mechanism may involve inhibition of CXCR-4 receptor function, because in BCR/ABL-transformed cells, CXCR-4 receptors were expressed on the cell surface, but SDF-1alpha calcium flux was inhibited. Because SDF-1alpha and CXCR-4 are felt to be involved in progenitor cell homing to marrow, the abnormality decribed here could contribute to the homing and retention defects typical of immature myeloid cells in chronic myelogenous leukemia.

Animals↗
PubMed1999

Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism.

BACKGROUND: Experimental and clinical evidence has demonstrated that the establishment of allogeneic chimerism after bone marrow transplantation may provide donor-specific tolerance for solid organ allografts. METHODS: Based on the preliminary results of a clinical trial using nonmyeloablative preparative therapy for the induction of mixed lymphohematopoietic chimerism, we treated a 55-year-old woman with end stage renal disease secondary to multiple myeloma with a combined histocompatibility leukocyte antigen-matched bone marrow and renal transplant after conditioning with cyclophosphamide, antithymocyte globulin, and thymic irradiation. RESULTS: The posttransplant course was notable for early normalization of renal function, the absence of acute graft-versus-host disease, and the establishment of mixed lymphohematopoietic chimerism. Cyclosporine, which was the only posttransplant immunosuppressive therapy, was tapered and discontinued on day +73 posttransplant. No rejection episodes occurred, and renal function remains normal on day + 170 posttransplant (14 weeks after discontinuing cyclosporine). Although there is presently no evidence of donor hematopoiesis, there is evidence of an ongoing antitumor response with a recent staging evaluation showing no measurable urine kappa light chains. The patient remains clinically well and is off all immunosuppressive therapy. CONCLUSION: This is the first report of the deliberate induction of mixed lymphohematopoietic chimerism after a nonmyeloablative preparative regimen to treat a hematological malignancy and to provide allotolerance for a solid organ transplant.

Bone Marrow Transplantation↗
PubMed1999

Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation.

BACKGROUND: HLA-mismatched donor bone-marrow transplantation after standard myeloablative conditioning therapy for haematological malignant disorders has been limited by severe graft-versus-host disease (GVHD) and graft failure. We tested a new approach to find out whether lymphohaemopoietic graft-versus-host reactions could occur without excessive GVHD in mixed haemopoietic chimeras produced across HLA barriers with non-myeloablative conditioning. METHODS: Five patients with refractory non-Hodgkin lymphoma underwent bone-marrow transplantation from haploidentical related donors sharing at least one HLA A, B, or DR allele on the mismatched haplotype. Conditioning included cyclophosphamide and thymic irradiation before transplantation, and antithymocyte globulin before and after transplantation. The only other GVHD prophylaxis was cyclosporin. FINDINGS: Four of five patients were evaluable and showed engraftment. Mixed haemopoietic chimerism was established, with a predominance of donor lymphoid tissue and varying degrees of myeloid chimerism. Two patients were in GVHD-free states of complete and partial clinical remission at 460 and 103 days after bone-marrow transplantation. INTERPRETATION: Mixed chimerism can be induced in adult recipients of HLA-mismatched bone-marrow transplantation by a non-myeloablative conditioning regimen. The antilymphoma responses seen in two patients suggest that allogeneic bone-marrow transplantation without myeloablative conditioning might have potent immunotherapeutic benefits.

Adult↗
PubMed1999

Late onset veno-occlusive disease following high-dose chemotherapy and stem cell transplantation.

The original definition of hepatic veno-occlusive disease (VOD), which is still widely accepted, includes onset of the clinical syndrome before day +20 following high-dose chemotherapy (HDC) and stem cell transplantation (SCT). We retrospectively identified four patients following HDC and SCT presenting with late onset VOD occurring at day +24, day +27, day +34 and day +42 post SCT. All patients had moderate VOD, with successful resolution of the VOD before day +100 with optimal supportive therapy. Common risk factors for VOD shared by all four patients included an older age (median age: 60 years), and use of a busulphan-containing regimen. Mean and maximum bilirubin levels for all patients during the VOD syndrome were 2.02, 1.76, 5.09, 2.87 mg/dl and 2.5, 2.2, 8.9 and 4.1 mg/dl, respectively, which correlated well with duration of VOD. All patients encountered platelet transfusion-dependent thrombocytopenia during VOD. Ursodeoxycholic acid was used as VOD prophylaxis beginning at a mean of 33 days prior to onset of VOD. As the cellular target of hepatic VOD is as yet unidentified, it is uncertain whether ursodiol or other common characteristics of patients with late onset VOD influence the pathogenesis and natural history of this disease. We believe that the uncommon clinical entity of late onset VOD, a potentially fatal regimen-related toxicity, should not be ignored as a diagnosis of liver disease after 3 or more weeks following HDC and SCT.

Aged↗
PubMed1999

A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation.

Pneumonia due to Pneumocystis carinii is an infrequent complication following autologous stem cell transplantation (ASCT) which is associated with a high mortality. Although administration of trimethoprim/sulfa- methoxazole (TMP/SMX) is an effective prophylactic strategy for Pneumocystis carinii pneumonia (PCP), treatment-associated toxicity frequently results in discontinuation of therapy. We have conducted a prospective randomized trial comparing atovaquone, a new anti-Pneumocystis agent, with TMP/SMX for PCP prophylaxis following autologous peripheral blood stem cell (PBSC) transplantation. Thirty-nine patients were studied. Twenty patients received atovaquone suspension and 19 patients received TMP/SMX. The median ages were 44 (range 20-68) and 47 (range 32-63) years, respectively. A similar number of patients with solid tumors (14 vs 15) and hematologic malignancies (five vs five) were treated in each group. Either TMP/SMX (160/800 mg) or atovaquone (1500 mg) was administered daily from transplant day -5 until day -1, discontinued from day 0 to engraftment, then resumed 3 days per week until day +100 post-transplant. The median time to engraftment (ANC >0.5 x 109/l) was similar in both groups. Eighty percent of the patients randomized to atovaquone prophylaxis completed the study. Four atovaquone-treated patients were removed from study; two patients (10%) did not receive a transplant and two patients (10%) were removed due to a protocol violation. None of the 16 patients treated with atovaquone experienced treatment-associated adverse effects. Of the 19 patients randomized to receive TMP/SMX, 55% completed the study. Nine TMP/SMX-treated patients were removed from the study; one patient (5%) did not receive a transplant and eight patients (40%) were removed due to drug intolerance (P < 0.003). The rate of intolerance to TMP/SMX led to the early discontinuation of this randomized trial. Intolerance of TMP/SMX included elevated transaminase levels (n = 1), nausea or vomiting (n = 3), thrombocytopenia (n = 2) and neutropenia (n = 2). All episodes of TMP/SMP intolerance occurred following transplantation after a median duration of 17.5 (range 2-48) days and a median of 7 (range 1-20) doses. Resolution of adverse side-effects occurred in all eight patients within a median of 7 (range 2-20) days following discontinuation of therapy. Neither PCP nor bacterial infections were identified in any of the patients treated. This prospective randomized study demonstrated that atovaquone is well-tolerated for anti-Pneumocystis prophylaxis in autologous PBSC transplant patients intolerant of TMP/SMX.

Adult↗
PubMed1997

A hematopoietic cell L-selectin ligand exhibits sulfate-independent binding activity.

L-selectin is a leukocyte cell-surface glycoprotein that mediates adhesive interactions between circulating cells and vascular endothelium. All endothelial ligands of L-selectin characterized to date are glycoproteins that require sulfation for activity and share reactivity with MECA 79, a monoclonal antibody that recognizes a sulfate-dependent epitope involved in L-selectin attachment. We have recently identified by functional assay a glycoprotein L-selectin ligand expressed on the human hematopoietic cell line KG1a. We report here that this ligand is not recognized by MECA 79 and that it retains binding activity after metabolic inhibition of sulfation by chlorate. A native membrane L-selectin ligand exhibiting sulfate-independent function has not been described previously. Identification of this novel ligand on a nonendothelial cell type suggests that structural determinants conferring L-selectin binding may vary in a cell- and tissue-specific manner.

Animals↗
PubMed1997

High-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with multiple myeloma and renal insufficiency.

Six patients with multiple myeloma and chronic renal insufficiency (serum creatinine >3.0 mg/dl), including four on dialysis, received high-dose busulfan and cyclophosphamide (BUCY) followed by autologous peripheral stem cell transplantation. Peripheral blood stem cells were collected after priming with cyclophosphamide, etoposide and G-CSF. Patterns of engraftment and toxicities were not apparently different from those seen in myeloma patients with normal renal function. There was one toxicity-related death, resulting from a massive spontaneous subdural hematoma. One patient died of disease progression 6 months after transplant, while the remaining four patients are alive and free of myeloma progression 6 to 39 months after high-dose therapy. Two of these patients have remained in complete remission for 28 and 39 months. Our experience suggests that high-dose therapy with BUCY and autologous peripheral blood stem cell rescue is feasible in patients with multiple myeloma and renal failure.

Adult↗
PubMed1997

Expression of an L-selectin ligand on hematopoietic progenitor cells.

The process of hematopoiesis is dependent on discrete cell-cell and cell-matrix interactions which are tightly regulated by expression of adhesion molecules. L-selectin, an adhesion protein best known for regulating leukocyte attachment to endothelium, is characteristically expressed on the earliest hematopoietic progenitor cells. Ligands for L-selectin have been extensively characterized on endothelial cells. We recently identified a ligand for L-selectin expressed on the human hematopoietic progenitor cell line KG1a. This molecule is an integral membrane glycoprotein which is structurally different from all ligands previously described. We hypothesize that this molecule may mediate L-selectin-specific adhesive interactions during hematopoiesis. This article discusses the biology of L-selectin and its ligands, and reviews our current understanding of the structure and distribution of the L-selectin ligand expressed on hematopoietic cells.

Acute Disease↗
PubMed1996

Cutaneous CD56+ large T-cell lymphoma associated with high serum concentration of IL-2.

We report the case of a patient with a clinically aggressive large cell lymphoma (LCL) which expressed several T-lymphocyte markers and, in addition, CD56 and, to a lesser degree, CD68 antigens. A marked increase in serum concentration of interleukin (IL)-2 was found (490 and 167 pg/0.1 mL in two serum samples collected 6 months apart). This increase in IL-2 appeared unique to this lymphoma because serum concentration of IL-2 was not increased in any of the cases of various types of cutaneous lymphoproliferative disorders tested: mycosis fungoides-related cutaneous T-cell lymphoma (CTCL: 28 patients), granulomatous slack-skin syndrome (GS-SS: 1 patient), anaplastic large cell lymphoma (ALCL: 2 patients), subcutaneous gamma/delta T-cell lymphoma (gamma/delta-TCL: 1 patient), adult-type leukemia/lymphoma (ATLL: 1 patient), and lymphomatoid papulosis (LyP: 4 patients). Furthermore, the increase in IL-2 serum concentration appeared selective in this CD56+ large-cell lymphoma-bearing patient, because concentration of none of the five other cytokines tested (IL-4, IL-6, IFNgamma, GM-CSF, and TNFalpha) was increased. In contrast, soluble receptors for IL-2 and two of the other cytokines (IL-6, and TNFalpha) were markedly increased not only in this patient, but also in most patients with the other cutaneous lymphoproliferative disorders that we examined except for lymphomatoid papulosis. These data indicate that increased IL-2 serum concentration may help to diagnose a unique type of cutaneous CD56(+) large (T-) cell lymphoma and suggest that IL-2 way play a role of an autocrine growth factor for this lymphoma.

Aged↗
PubMed1995

Evidence of post-transcriptional regulation of L-selectin gene expression in rat lymphoid cells.

Early investigations of lymphocyte migration in the rat operationally identified a lymphocyte membrane protein, designated 'A.11', which mediates lymphocyte adherence to lymph node (LN) high endothelial venules (HEV). To determine the primary structure of A.11 and examine its expression in lymphoid cells, we constructed an expression phage cDNA library of rat thoracic duct lymphocytes (TDL) and performed screening by immunoselection (utilizing an anti-A.11 polyclonal antiserum) as well as by hybridization selection. We have isolated a approximately 1.6 kb clone, RS-2, and sequencing revealed that it encodes rat L-selectin. The clone contains the complete coding sequence, a 105-bp 5' untranslated region and a 359-bp 3' untranslated region. Transfection of RS-2 cDNA into 70Z/3 cells conferred binding to HEV concomitant with expression of A.11, providing direct evidence that A.11 is rat L-selectin. Metabolic radiolabelling studies revealed that thymocytes synthesize markedly less L-selectin than do TDL or LN lymphocytes. However, Northern blot studies using RS-2 as a probe indicate that thymocytes possess more L-selectin RNA than does TDL. Together, these data provide evidence that post-transcriptional events contribute to regulation of L-selectin expression in thymocytes.

Amino Acid Sequence↗
PubMed1995

The effects of corticosteroids on lymphocyte recirculation in humans: analysis of the mechanism of impaired lymphocyte migration to lymph node following methylprednisolone administration.

BACKGROUND: Steroid therapy profoundly inhibits lymphocyte migration into lymph nodes (LN), thereby disrupting lymphocyte recirculation. This study was undertaken in human subjects to examine two nonmutually exclusive hypotheses proposed to explain this steroid effect: (1) steroids decrease the capacity of LN high endothelial venules (HEV) to support lymphocyte adherence; and/or (2) steroids alter the expression of lymphocyte adhesion molecules specific for entry into LNs. METHODS: Human LNs were obtained from cadaveric organ donors before and after methylprednisolone infusion and examined for their capacity to support lymphocyte adherence using an in vitro lymphocyte-HEV adherence assay. Additionally, six healthy volunteers underwent infusions of saline (placebo) and methylprednisolone (3 mg/kg in saline), and peripheral blood lymphocytes were isolated before, immediately after, and at 1, 2, 4, 8, 24, and 48 hours following infusions. At each timepoint, flow cytometric analysis of lymphocyte L-selectin, CD44, and LFA-1 expression was assessed. Short-term tissue culture studies were also performed to examine the direct effects of steroids on the expression of these lymphocyte proteins. RESULTS: LNs obtained from organ donors before and after steroid infusion displayed no differences in the capacity of HEV to support lymphocyte adherence. In controlled steroid infusion studies, lymphopenia was observed within 1 hour and persisted for 8 hours. Cells isolated during the period of lymphopenia did not adhere to LN HEV, and there was a marked decrease in both the percentage and mean fluorescence intensity level of L-selectin+ lymphocytes; minor changes were observed in the percentage of CD44+ and LFA-1+ cells, while the mean fluorescence intensity level decreased for CD44+ cells and increased for LFA-1+ cells. All such changes in adhesion protein levels among circulating cells reversed with the resolution of lymphopenia. However, in tissue culture experiments, steroids did not alter the expression of lymphocyte adhesion proteins. CONCLUSIONS: The decreased migration of lymphocytes to LN following steroid administration is not due to changes in the capacity of HEV to bind lymphocytes, but results from decreases in the level of L-selectin expressed among circulating cells. Culture studies suggest that steroids do not directly alter lymphocyte adhesion protein expression. The possibility that these agents act indirectly by stimulating the release and/or promoting the activity of relevant biologic mediators affecting lymphocyte adhesion protein expression needs further exploration.

Adult↗
PubMed1994

Detection of an L-selectin ligand on a hematopoietic progenitor cell line.

L-selectin, the peripheral lymph node "homing receptor," is an adhesion protein that mediates lymphocyte binding to lymph node high endothelial venules. Ligands for this protein have been identified only on endothelial cells, and recent murine studies indicate that CD34 on endothelial cells is an L-selectin ligand. To investigate whether CD34 expressed on hematopoietic cells functions as an L-selectin ligand, we used an in vitro binding assay to examine lymphocyte adherence to KG1a, a CD34+ human hematopoietic progenitor cell line. We observed specific L-selectin-mediated adherence of lymphocytes to KG1a: the binding was calcium-dependent, was strictly inhibited by anti-L-selectin antibodies and by carbohydrate ligands of L-selectin, and was abrogated by induction of L-selectin shedding from the lymphocyte membrane by treatment with phorbol esters. However, blocking studies using anti-CD34 antibodies, and experiments using KG1a cells sorted for CD34 expression and COS-7 cells transfected with full-length CD34 cDNA indicate that the ligand on KG1a is not CD34; moreover, RPMI 8402, a CD34+ cell line, does not support lymphocyte adherence in the binding assay. Treatment of KG1a with the enzymes neuraminidase, chymotrypsin, and bromelain abrogated lymphocyte binding to the cells, indicating that the ligand is a glycoprotein. These experiments show that CD34 on hematopoietic cells is not an L-selectin ligand and provide the first evidence of a ligand for L-selectin present on a non-endothelial cell.

Antigens, CD↗
PubMed1993

Physiologic migration of lymphocytes to lymph nodes following bone marrow transplantation: role in immune recovery.

The transplantation of bone marrow requires the recipient to create a new immune system as stem cells divide and differentiate into lymphocyte effector cells. The establishment of host immune capabilities posttransplant is critically dependent on the migration of immature and mature lymphocytes to lymph nodes, as these tissues function principally to promote lymphocyte maturation and differentiation into immunologic effectors. The first step in the directed migration of lymphocytes into lymph nodes is the attachment of the cells to lymph node high endothelial venules (HEVs), and the molecular basis of this interaction is well characterized. Experimental evidence indicates that bone marrow transplantation results in perturbations in the migration of lymphocytes to lymph nodes by affecting lymphocyte-HEV adherence: pretransplant conditioning regimens have toxic effects on HEV that decrease their capacity to support lymphocyte adherence, and the use of pharmacologic agents post-transplant may be associated with alterations in the level of expression of lymphocyte membrane adhesion proteins that mediate attachment to HEV. A greater understanding of these effects should lead to development of transplant regimens that preserve the physiologic trafficking of lymphocytes to lymph node, thereby accelerating the rate of immunologic recovery following transplant.

Animals↗
PubMed1991

Lymphocyte-homing receptors and preferential migration pathways.

Over the next few years, research can be expected to focus on the regulation of expression of the tissue-specific homing receptors, the molecular nature of the corresponding endothelial ligands, and the spectrum of factors regulating the adhesiveness of high endothelial venule cells in vivo. In addition, it would be important to elucidate whether other adhesion molecules also play a role in tissue-specific lymphocyte entry and localization into distinct regions of the lymphoid organ. The results of these studies should provide important insights into the mechanisms controlling lymphocyte trafficking into lymphoid tissues as well as chronic inflammatory sites.

Cell Adhesion↗