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Biomedical subjects

G Pierson

Publications and source records attributed to G Pierson.

14 recordsLinked to original sources
PubMed2006

Unrelated donor or partially matched related donor peripheral stem cell transplant with CD34+ selection and CD3+ addback for pediatric patients with leukemias.

Unmodified peripheral stem cell transplants are associated with an increased risk of extensive chronic GVHD. T depletion may reduce this risk, but the risk of graft failure or relapse may increase. To decrease the risks of both extensive chronic GVHD and graft failure, we added back a defined dose of CD3+ cells to CD34+ selected PSCs. Twenty-four patients were evaluable for outcome analysis. Donors were unrelated (23) or related (1). Conditioning was thiotepa, cyclophosphamide, and total body irradiation. Cyclosporine was used post transplant. Following CD34+ selection, a total of 5 x 10(5)/kg CD3+ cells were infused. Donors were matched for 12 patients. The median CD34+ dose infused was 7.1 x 10(6)/kg. Engraftment occurred in all patients at a median of 14 days (10-19). Twelve patients are alive in remission 15-34 months (median, 25) post PSCT. GVHD occurred in 17 patients, but was >grade II in only 2. Chronic GVHD occurred in 61.5% of evaluable patients, but was limited to skin and perioral cavity. Two patients relapsed, and 10 patients died of non-relapse causes. This study demonstrates that PSCT with CD34+ selection and a defined dose of CD3+ results in prompt engraftment and may limit development of extensive chronic GVHD.

Adolescent↗
PubMed2005

Outcomes of transplantation with partial T-cell depletion of matched or mismatched unrelated or partially matched related donor bone marrow in children and adolescents with leukemias.

Graft-versus-host disease (GVHD) remains a major barrier to successful hematopoietic stem cell transplant for patients who lack a matched related donor. Partial T-cell depletion (TCD) of the graft may decrease the risk of severe GVHD with unrelated donors (URD) and partially matched related donors (PMRD) while retaining an antileukemic effect. We analyzed our experience using URD and PMRD for pediatric patients with leukemias from 1990 to 2001. A subgroup of 'matched' URD donor pairs was retrospectively analyzed for high-resolution class I. Partial TCD was accomplished with monoclonal antibody T10B9 or OKT3 and complement. There were 76 URD (45% matched) and 28 PMRD recipients. Event-free survival (EFS) was 38.3%, and overall survival (OS) 45.1% at 3 years. On multivariate analysis, there was no difference in survival based upon marrow source, but nonrelapse mortality was higher with the use of PMRD. Relapse occurred in 6% of ALL patients, and 22.8% of AML/MDS patients. Grades III-IV GVHD was observed in only 6.7% of patients. Partial TCD allows use of matched or mismatched URD, or PMRD with little mortality from GVHD, durable engraftment, and no increase in relapse risk.

Adolescent↗
PubMed2005

Unrelated donor bone marrow transplantation for children with severe aplastic anemia: minimal GVHD and durable engraftment with partial T cell depletion.

Both increased graft rejection and increased graft vs host disease (GVHD) remain obstacles to success for unrelated donor (URD) BMT for patients with SAA. Partial T cell depletion (PTCD) may decrease the risk of severe GVHD, while still maintaining sufficient donor T lymphocytes to ensure engraftment. We report on 12 patients with SAA who underwent PTCD URD BMT. All patients had failed medical therapy or relapsed following initial responses, and were transfusion dependent. The median age was 6 years, and there were five males. Donors were matched for four patients, and mismatched for eight. All patients received total body irradiation with either Ara-C or thiotepa and cyclophosphamide. PTCD was accomplished using monoclonal antibody T10B9 or OKT3 and complement. All patients engrafted, with a median time of 18 days to ANC >500. Only one patient had greater than grade II acute GVHD; two patients had limited and one patient extensive chronic GVHD. Nine patients are alive and transfusion independent at a median months post BMT. Three patients died from infection or renal failure. This series suggests that an aggressive immunosuppressive conditioning regimen with PTCD results in successful engraftment and minimal GVHD in pediatric patients with SAA, even with HLA mismatched donors.

Adolescent↗
PubMed2001

Angiogenesis inhibitor TNP-470 during bone marrow transplant: safety in a preclinical model.

High-dose therapy with stem cell rescue is a treatment option for patients with advanced solid tumors. Although this approach has promise for some pediatric cancers, especially neuroblastoma, it is limited by the risk of relapse posttransplant as well as concern about possible reinfused tumor cells in autologous stem cell products. Antiangiogenic agents given during and after recovery from high-dose therapy with stem cell rescue may decrease the risk of relapse. TNP-470 is an antiangiogenic agent now in clinical trials. Although it inhibits the growth of bone marrow (BM) colony-forming cells in vitro, no significant hematological toxicity has been seen in Phase I trials. To assess the feasibility of using antiangiogenic agents during the period of posttransplant hematopoietic engraftment, we have developed a model of stem cell transplant in mice. Mice were lethally irradiated and then rescued with stem cells containing a transgene expressed in the hematopoietic lineage. Mice were then treated with TNP-470 or placebo, and assessed for survival, successful engraftment, and kinetics of engraftment. Both treated and control mice demonstrated reliable multilineage engraftment as well as normal lymphoid maturation with no excess mortality in the treated group. WBCs were lower but still within the normal range at d+28 in mice treated with bolus TNP-470, but not in those treated with continuous infusion TNP-470, compared with controls. These data indicate that inhibitors of angiogenesis do not adversely impact engraftment after stem cell transplantation.

Angiogenesis Inhibitors↗
PubMed2000

CD34 selection as a stem cell purging strategy for neuroblastoma: preclinical and clinical studies.

BACKGROUND: The suitability of CD34 selection for purging peripheral blood progenitor cells (PBPC) collected from patients with neuroblastoma (NB) has been called into question, largely because of reports of detection of low levels of CD34 on the surface of some NB cell lines and tumors. PROCEDURE: We used three approaches to address the issue of purging of NB from stem cell specimens and possible labeling of NB: 1) Flow cytometric detection of CD34 on NB cell lines. We assessed CD34 expression using a panel of anti-CD34 monoclonal antibodies (MoAbs) including 9C5, 12.8, and QBend10 and showed no increase in labeling over secondary-only control. 2) Spiking experiments with the Isolex 50 system. NB cell lines were used to contaminate aliquots of PBPC collections, after which the products were purified using the Isolex 50. Purging of NB was assessed by quantitative multiplex RT-PCR (TaqMan system) using a tumor-specific transcript, GAGE. We demonstrated >2 logs of tumor cell depletion from these specimens. 3) Analysis of clinical specimens. PBPC pre- and post-CD34 selection were analyzed from patients treated on the CHP-594 transplant trial. RESULTS: In nine specimens selected using the Ceprate LC CD34 selection system where tumor was detectable by immunocytochemistry preselection, we observed >2.4 to >4.6 logs of NB purging after selection. We then analyzed 23 aliquots of PBPC infused into patients post-CD34 selection and compared them to the product preselection; 20/23 specimens showed depletion of NB, although some level of GAGE message was observed in most post-CD34 selection specimens. CONCLUSION: These data show that purging of NB from PBPC specimens using CD34 selection is feasible, yielding infused products that are negative at the level of ICC but often positive at the level of RT-PCR.

Antigens, CD34↗
PubMed1996

Use of a lethally irradiated major histocompatibility complex nonrestricted cytotoxic T-cell line for effective purging of marrows containing lysis-sensitive or -resistant leukemic targets.

Improved marrow purging protocols are needed in autologous bone marrow transplantation (BMT) to achieve complete eradication of minimal residual disease. This study investigates the potential of a human major histocompatibility complex (MHC) nonrestricted killer T-cell line (TALL-104) as a new marrow purging agent in a clinical setting. TALL-104 cells can be irradiated without losing cytotoxic activity against tumor targets in vitro. In vivo, the irradiated killers can be adoptively transferred into immunodeficient and immunocompetent leukemia-bearing mice, and reverse their disease even in advanced stages. The present study shows that gamma-irradiated TALL-104 cells, cultured for 18 hours with marrows from healthy donors, do not impair the viability and long-term growth of committed and pluripotent hematopoietic progenitors. However, as determined by polymerase chain reaction (PCR) and colony assays, TALL-104 cells could completely purge marrows containing up to 50% lysis-susceptible myelomonocytic leukemia cells (U937). When marrows were admixed with a pre-B leukemia cell line (ALL-1), which is fairly resistant to TALL-104 cell lysis in longterm 51Cr-release assays but can be totally growth inhibited by TALL-104 cells in proliferation assays, residual ALL-1 cells were detectable by PCR after TALL-104 purging. However, importantly, these PCR+ marrows were devoid of tumorigenic activity when transplanted into the human hematopoietic microenvironment of human severe combined immunodeficient (SCID) chimeras. These data indicate the strong potential of the TALL-104 cell line in future marrow purging strategies against lysis-susceptible and -resistant leukemias.

Animals↗
PubMed1993

T-cell-depleted maternal bone marrow transplantation for siblings with X-linked severe combined immunodeficiency.

Prenatal diagnosis of X-linked severe combined immunodeficiency in a male fetus made possible elective neonatal bone marrow transplantation before onset of symptoms. Bone marrow transplantation was performed by using T-cell-depleted maternal marrow that had been cryopreserved 2 years earlier, at the time that his older affected brother underwent transplantation. The second patient had less morbidity and more rapid reconstitution of his immune function.

Alleles↗
PubMed1988

Spontaneous hydrogen peroxide release from alveolar macrophages of patients with active sarcoidosis: comparison with cigarette smokers.

Alveolar macrophages from patients with active pulmonary sarcoidosis have been shown to secrete several factors, such as interleukin-1 and alveolar macrophage-derived growth factor. We examined alveolar macrophages from nonsmoking patients with sarcoidosis undergoing bronchoalveolar lavage (BAL) for evaluation of disease activity. We compared these cells with macrophages from smoking and nonsmoking control patients. The amount of hydrogen peroxide released by the macrophages either spontaneously or after stimulation by phorbol myristate acetate was measured. The alveolar macrophages from smokers spontaneously released hydrogen peroxide, as we previously observed. The macrophages from the patients with sarcoidosis also released detectable amounts of hydrogen peroxide, but the macrophages from the non-smokers did not. Alveolar macrophages from all three groups released hydrogen peroxide when stimulated with phorbol myristate acetate. The macrophages from all three groups were examined for the presence on the surface membrane of beta-galactosidase, an enzyme that appears on the surface of older, activated macrophages. The macrophages in the BAL fluid of the patients with sarcoidosis had less beta-galactosidase staining than did those from the smokers, although they released comparable amounts of hydrogen peroxide. These findings suggest that alveolar macrophages in the BAL fluid of patients with sarcoidosis are younger, more monocyte-like, and activated by various factors, including gamma-interferon.

Humans↗
PubMed1986

The rat testicular A1 adenosine receptor-adenylate cyclase system.

When adenosine interacts with membrane-bound A1 receptors, it is capable of inhibiting the enzyme adenylate cyclase in brain and fat tissue. In this paper we characterize the A1 adenosine receptor-adenylate cyclase system of the rat testes. The agonist radioligand (-)-N-[3-[125I]iodo-4-hydroxyphenyl-(isopropyl)adenosine binds with high affinity (Kd, congruent to 1 nM) in a saturable manner (maximum binding, congruent to 600 fmol/mg protein). The A1 adenosine receptor binding displays the appropriate pharmacology, stereospecificity, and sensitivity to guanine nucleotides. The testicular A1 receptor is also coupled in an inhibitory manner to the enzyme adenylate cyclase, as demonstrated by the ability of N6-R-phenyl-2-propyladenosine to inhibit isoproterenol- and forskolin-stimulated cAMP accumulation. The testicular A1 receptor can be solubilized in high yield and in an active form with the detergent digitonin. The solubilized receptor retains all of the pharmacological properties of the membrane-bound receptor. Although there are many similarities among the A1 receptor from testes, brain, and fat tissue, the testicular A1 receptor displays a larger apparent mol wt. By photoaffinity labeling, the A1 adenosine receptor-binding subunit of fat and brain are 38,000 mol wt proteins, while the testicular A1 receptor binding subunit is a 42,000 mol wt protein.

Adenosine↗
PubMed1982

Recognition of human minor alloantigen(s) by cytotoxic lymphocytes in vitro.

Lymphocytes from an extensively transfused patient with aplastic anemia were induced to cytotoxicity against target cells from several HLA-matched siblings by in vitro stimulation with allogeneic cells. Effective stimulating cells shared HLA-B7 with the patient, but not all B7 individuals were effective. An additional factor, which was found to segregate in both the patient's and an unrelated sibship, was also necessary. Segregation of this minor alloantigen, W, was also revealed among the patient's HLA-matched sibs by differential susceptibility to lysis by effectors from the patient. The ratio of six positive to four negative siblings suggests that the antigen difference might be coded by a single locus. Lymphocytes from a normal sib, who like the patient is lacking the minor antigen, could not be induced to cytotoxicity against positive targets. Thus in vivo sensitization of the donor of the responding cells appears to be necessary for the demonstration of the cytotoxic response to the minor antigen in vitro. No correlation was observed between the segregation pattern of W and of known blood group antigens, and no cytotoxic antibody to W was detected in the patient's serum in several trials.

Adult↗