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Biomedical subjects

R Storb

Publications and source records attributed to R Storb.

At least 523 records · Page 29Linked to original sources
PubMed1985

Is the leukocyte group-5a antigen associated with reduced NK cell function?

The leukocyte group-5a antigen has an increased frequency in lymphoid malignancy. We have investigated the possibility that expression of this antigen is associated with diminished or reduced natural killer function since natural killer cells are believed to represent a vital component of protection against developing malignancy. Natural killer function of a group of 18 subjects who expressed the group-5a antigen on their cells was substantially lower than that of a group of 24 subjects who did not express 5a.

Adolescent↗
PubMed1985

Graft-versus-host disease in dog and man: the Seattle experience.

In dog and in man a marrow graft from a donor genetically identical for the major histocompatibility complex is followed by significant graft-versus-host disease (GvHD) in approximately one-half of the recipients, despite the administration of post-grafting immunosuppressive therapy. Controlled trials comparing post-grafting therapy using methotrexate or cyclosporine have shown no difference in long-term survival, although cyclosporine reduces the incidence of mucositis and is associated with somewhat earlier engraftment. Observations in the canine model indicating efficacy of a combination of a brief course of methotrexate with the cyclosporine regimen are now being tested in patients, with early results indicating a reduction in GvHD and an improved survival. In both species, failure to administer immunosuppression after grafting is associated with a high incidence of acute GvHD and an adverse effect on survival. Removal of donor T cells from the marrow inoculum may reduce the incidence of acute GvHD but at the price of a higher likelihood of subsequent graft failure. Studies of canine and human chimeras are in agreement with murine data indicating a principal role for T cells in the pathogenic mechanism of GvHD. Chimera lymphocytes (of donor origin) from dogs and patients with acute GvHD proliferate in response to previously stored host cells, and lymphocytes cytotoxic to host target cells are seen in patients with GvHD. Our observations indicate a direct, rather than an indirect, role for T cells since lymphocytes from donors sensitized to chimeric skin grafts can cause lethal GvHD when infused into stable chimeric recipients. "Specific" suppressor cells may play a role in maintaining stable graft-host tolerance while "nonspecific" suppressor cells may be responsible for the impaired immune defenses in patients with chronic GvHD. Chronic GvHD, which resembles systemic collagen vascular disease, occurs in approximately 40% of matched recipients, particularly following acute GvHD, and is more frequent in older patients. Efforts to treat both acute and chronic GvHD with steroids, antithymocyte globulin, cyclosporine and azathioprine are only partially and unpredictably effective. Data in dogs pointed out the feasibility of transplants from partially matched related donors or matched unrelated donors, an approach that is now being actively pursued in human patients. Marrow transplants from HLA-partially matched family members resulted in a higher incidence of acute GvHD.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMed1985

Allogeneic marrow transplantation in the treatment of MOPP-resistant Hodgkin's disease.

Eight patients with disseminated Hodgkin's disease resistant to MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) chemotherapy were treated with high-dose chemoradiotherapy and marrow transplantation from an HLA-identical sibling. Two patients remain alive in unmaintained complete remission (CR) at 38 and 39 months after transplant. In the other six patients, reasons for failure included relapse of lymphoma (two patients), or death due to complications of the transplant procedure, including Legionnaire's disease, disseminated zoster, graft-v-host disease, and aspiration pneumonia secondary to severe mucositis. These results demonstrate that some patients with MOPP-resistant Hodgkin's disease can obtain prolonged CR following intensive chemoradiotherapy and allogeneic marrow transplantation.

Adult↗
PubMed1985

Immunogenetic aspects of a canine breeding colony.

A colony of dogs was expanded by selective breeding to study the immunogenetic determinants coded for by the major histocompatibility complex (DLA). Polymorphic determinants were identified by alloantisera specific for DLA-A and B loci antigens and by the mixed lymphocyte culture (MLC) which defined alleles at the D locus. Thirteen families totaling 58 offspring were produced and typed for allelic determinants coded for by each of the three gene loci. Allelic segregation in a codominant manner occurred as expected and a recombinant between the A and B loci was detected. A number of animals were homozygous at one or more loci, thus providing genetically standardized animals as a source of typing cells, antigens, and sera to further study the immunogenetic details of DLA and for in vivo studies in transplantation biology.

Alleles↗
PubMed1985

Marrow transplantation for chronic myelocytic leukemia: a controlled trial of cyclosporine versus methotrexate for prophylaxis of graft-versus-host disease.

Forty-eight patients with chronic myelocytic leukemia, aged 11 to 47, were treated with high-dose cyclophosphamide and fractionated total body irradiation, followed by infusion of marrow from HLA-identical siblings. They were randomized to receive either methotrexate (MTX) (n = 23) or cyclosporine (CSP) (n = 25) as postgrafting prophylaxis for graft-v-host disease (GVHD). All patients had evidence of sustained hematopoietic engraftment. Seventeen of the 25 patients receiving CSP and 17 of the 23 patients receiving MTX are alive between one and almost four (median, 1.7) years, with an actuarial survival rate at three years of 62% and 66%, respectively (P = .60). Also, with respect to most other parameters studied, the two drugs were identical. The probability of acute GVHD was .42 and .46, respectively (P = .70), that of chronic GVHD, .50 and .63 (P = .44), and that of death from transplant-related causes, .30 and .24 (P = .51). There were no differences in the speed of granulocyte and platelet engraftment (P = .82 and .94, respectively), and the duration of hospitalization was comparable (P = .58). Patients receiving MTX required red cell transfusions for a shorter period of time (P = .02), but had a slightly increased morbidity from early oral mucositis. The leukemia recurrence rates were comparable (P = .60). With the regimens used in this study, we conclude that CSP failed to reduce the incidence of GVHD and improve the survival of patients with chronic myelocytic leukemia when compared to results with standard MTX.

Adolescent↗
PubMed1985

Monoclonal antibody to human cytotoxic-suppressor T-lymphocytes cross-reacts with canine lymphocytes and inhibits cell-mediated lympholysis of canine cells.

Of 19 murine antihuman Tp32 (T8) monoclonal antibodies tested, only antibody T811 showed cross-reactivity with canine lymphoid cells. It recognized an antigen expressed on 19%-27% of peripheral blood mononuclear cells (PBMC), 20%-30% of peripheral Thy 1+ T-lymphocytes, 40% of puppy thymocytes, 35%-45% of alloantigen-activated peripheral lymphocytes, and 100% of PBMC from a dog with acute T-cell leukemia. The antigen was not expressed on peripheral Thy 1- cells, bronchoalveolar cells, or null-type acute leukemia cells. The antibody inhibited cell-mediated lympholysis in the absence of complement, while antibody F3-20-7 directed at the canine Thy 1 antigen did not. It was not possible to precipitate a corresponding cell surface antigen on canine cells using standard 125I radioimmunoprecipitation techniques nor did the antibody cause antigenic modulation. Our data suggest that monoclonal antibody T811 reacts with a functional subset of canine T-lymphocytes similar to that of human cells; however, significant differences may exist between the antigens recognized on these cells in the two species.

Animals↗
PubMed1985

The regulation of immunoglobulin synthesis after HLA-identical bone marrow transplantation: VI. Differential rates of maturation of distinct functional groups within lymphoid subpopulations in patients after human marrow grafting.

This investigation uses different polyclonal activators of in vitro immunoglobulin production to elicit immunoregulatory profiles of B cells, T cells, T4 cells, and T8 cells from 25 recipients (13 with and 12 without chronic graft-v-host disease [GVHD] ) after HLA-identical marrow transplantation for aplastic anemia or hematologic malignancy. Pokeweed mitogen, Epstein-Barr virus, herpes simplex type 1 virus, and tetanus toxoid were used to induce immunoglobulin production as measured by a plaque assay. Multiple defects in the various lymphoid subsets were found in both groups of patients. There was defective b cell function, lack of T cell or T4 cell subset helper activity, and increased T cell, T4 cell, or T8 cell suppressor activity after stimulation with the various activators. Inconsistent B, T, T4, and T8 cell functions in the marrow graft recipients provide evidence for (a) different functional groups of cells within each subset responsive to different polyclonal activators; (b) a spectrum of immune capabilities within each phenotype lineage; (c) different patterns of immune reconstitution for each lymphocyte subset after marrow grafting; and (d) chronic GVHD altering recovery of in vitro functional responses to the different polyclonal activators.

B-Lymphocytes↗
PubMed1985

A randomized trial of antihuman thymocyte globulin versus murine monoclonal antihuman T-cell antibodies as immunosuppressive therapy for aplastic anemia.

A prospective randomized trial was undertaken to compare the efficacy and toxicity of murine antihunman T-cell monoclonal antibody (mcAb) therapy to that of horse antihuman thymocyte globulin (ATG) in the treatment of severe aplastic anemia (AA). Patients were randomized into one of the two treatment groups as well as to receive or not receive androgens. Median duration of aplasia prior to treatment was 1.5 and 2.2 months for the mcAb and ATG groups, respectively. One of 12 patients who received mcAb therapy had a partial response, whereas four of 13 patients receiving ATG had a complete or partial response. Of the 11 patients who failed mcAb treatment, six were subsequently treated with ATG and two improved. Ten of 13 patients who received ATG are surviving compared with seven of 12 patients who received mcAb. Toxicity of mcAb therapy was less than that of ATG. Future studies are needed to determine whether mcAbs known to be immunosuppressive are of benefit as therapy for patients with AA.

Adolescent↗
PubMed1985

Cellular interactions in marrow-grafted patients. III. Normal interleukin 1 and defective interleukin 2 production in short-term patients and in those with chronic graft-versus-host disease.

Peripheral blood mononuclear leukocytes (cells of marrow donor origin) from 89 patients were collected at various times after allogeneic marrow transplantation, stimulated in vitro by phytohemagglutinin, and assayed for the production of interleukin 2 (IL-2). This was done by testing culture supernatants for their ability to induce proliferation of human lymphoblasts and/or IL-2-dependent cultured murine cytotoxic cells. Supernatants from cultures of patient cells were compared with those of marrow donor cells. Supernatants produced by cells from most short-term marrow recipients (30-101 days postgrafting), regardless of the presence or absence of acute graft-versus-host disease (GVHD), and those from most long-term patients with chronic GVHD (103-1932 days postgrafting) had significantly lower-than-normal IL-2 activity, whereas cells from most long-term marrow recipients without GVHD (353-1934 days postgrafting) had essentially normal IL-2 activity. Additionally, we tested the ability of monocytes from 35 marrow recipients to produce interleukin 1 (IL-1) in response to lipopolysaccharide as compared with monocytes from marrow donors or normal unrelated individuals. IL-1 activity in culture supernatants of patient cells, regardless of the time of testing after marrow grafting and the status of GVHD, was found not to differ from that in supernatants of normal cells. These findings suggest that impaired T cell functions seen in some (but not all) marrow recipients are probably not due to IL-1 but to IL-2 deficiency or to the mechanism that causes IL-2 deficiency.

Adolescent↗
PubMed1985

Recurrence of aplastic anemia following cyclophosphamide and syngeneic bone marrow transplantation: evidence for two mechanisms of graft failure.

Two patients with aplastic anemia were treated with high-dose cyclophosphamide and marrow transplantation from their normal, genetically identical twin. Both patients rapidly recovered normal marrow function, but marrow failure recurred 13 and 18 months later. Because donor and host pairs were identical twins, these cases of graft failure could not have resulted from the usual cause of graft failure, ie, immunological reactivity of host cells against unshared minor histocompatibility antigens of the donor. These results imply that there are at least two mechanisms responsible for graft failure after marrow transplantation for severe aplastic anemia.

Adult↗
PubMed1985

Failure of autologous marrow reconstitution after cytolytic treatment of marrow with anti-Ia monoclonal antibody.

Hematopoietic stem cell toxicity of the murine monoclonal antibody 7.2, recognizing Ia-like antigens on canine cells, was tested in an autologous bone marrow transplantation model. Dogs were given 9.2 Gy of total body irradiation followed by the infusion of autologous marrow treated by one of two methods to remove Ia+ cells. In six dogs, the marrow cells were pelleted, treated with antibody 7.2 (1:1,000) and rabbit complement (1:4), resuspended in culture medium, and infused. All six dogs had prompt and sustained engraftment surviving greater than 26 days. Indirect immunofluorescence showed, however, that the depletion of Ia+ cells was incomplete. Four dogs received marrow cells first separated by density gradient centrifugation and then treated with an excess of antibody 7.2 and two cycles of undiluted rabbit complement. None of these dogs, surviving 17 to 22 days, had sustained engraftment. With antibody 7.2 used as the marker, only one dog had detectable residual Ia+ cells (0.9%) after treatment. Dogs receiving marrow cells obtained by density gradient centrifugation without additional manipulation, or with subsequent treatment with complement only or with complement and an antibody (DT-2) directed at a subpopulation of T cells, engrafted promptly and completely. We conclude that Ia+ bone marrow cells are essential for the successful engraftment of transplanted marrow in dogs.

Animals↗
PubMed1985

Autologous marrow transplantation in patients with acute nonlymphocytic leukemia in first remission.

Thirteen patients with acute nonlymphocytic leukemia underwent autologous bone marrow transplantation (ABMT) following high doses of cyclophosphamide and total body irradiation while in first complete remission. After marrow infusion four patients received human leukocyte interferon and nine received intravenous methotrexate. One patient died on day 16 of septicemia associated with severe gastrointestinal toxicity. In the remaining 12 patients the median day of achieving a circulating granulocyte level of 500/mm3 was 29 (range 15-94 days). Eight of 12 evaluable patients achieved a sustained platelet count of 20,000/mm3 or greater in a median of 44 days (range 12-116 days) and four patients did not achieve this level before death on days 116-396. One patient died on day 116 of interstitial pneumonitis secondary to cytomegalovirus. Eight patients relapsed 58-365 days after AMBT (median 335 days), and all have died. Three patients are alive and well without relapse 26-50 months after ABMT. This study demonstrated that poor engraftment was a frequent complication of ABMT when early posttransplant cytotoxic therapy was attempted. Relapse of leukemia and the number of long-term survivors in this small group of patients was not different from that expected following conventional therapy.

Acute Disease↗
PubMed1985

Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia.

Seventy-five patients, 13 to 49 years of age, with acute nonlymphoblastic leukemia in first remission were treated with cyclophosphamide, fractionated total body irradiation, and marrow transplantation from an HLA-identical sibling and randomized to receive either cyclosporine (CSP) (n = 36) or methotrexate (MTX) (n = 39) as prophylaxis for graft-v-host disease (GVHD). All patients engrafted, and 22 who were given CSP and 21 who were given MTX, are alive at 20 to 47 (median, 35) months (P = .5). Engraftment as assessed by granulocyte recovery (P less than .0005) and platelet transfusion requirement (P = .01) was faster in patients on CSP. Twelve patients (33%) on CSP and 22 (56%) on MTX developed acute GVHD of grades II through IV (P = .07) and 15 of 30 on CSP and 14 of 32 on MTX that were at risk developed chronic GVHD. The most frequent causes of death were interstitial pneumonitis and marrow relapse of leukemia, which occurred with similar frequency in both groups. Beneficial effects observed in patients on CSP included less severe mucositis and shorter duration of hospitalization; adverse effects included renal function impairment and hypertension. These data confirm that CSP is a useful immunosuppressant in patients undergoing marrow transplantation but fail to show a significant improvement in survival as compared with the standard regimen of MTX.

Acute Disease↗
PubMed1985

Marrow transplantation for children in first remission of acute nonlymphoblastic leukemia: an update.

Thirty-eight children between the ages of 0.8 and 17 years with acute nonlymphoblastic leukemia in first remission induced by chemotherapy were given cyclophosphamide, total body irradiation, and bone marrow transplants from HLA-matched donors. Six patients died of pneumonia, one died of metabolic problems, and one died of chronic graft-v-host disease complications. Five patients relapsed between six months and 3.2 years after transplantation. Three of the five died of leukemia, one survives with leukemia three years after transplantation, and one survives in remission off treatment following chemotherapy for 22 months. Twenty-five survive in continuous remission from 1.7 to 8.4 years after transplantation, and the actuarial analysis shows a disease-free survival rate of 64%, with a plateau extending from 3.5 to 8.4 years. All lead normal lives.

Actuarial Analysis↗
PubMed1985

Marrow transplantation for treatment of pregnancy-associated aplastic anemia.

This report describes the results of marrow transplantation in four patients with aplastic anemia during the last trimester of their pregnancies. All patients were treated with supportive care until delivery. Because of persistent severe aplasia, marrow transplantation was then performed 1.6-11.0 months postpartum. Marrow donors were HLA-identical siblings. Although all were at increased risk for graft rejection because of their pregnancies as well as their long transfusion histories, two patients were successfully engrafted and now survive 12 and 95 months after transplant. The other two patients rejected their grafts despite attempts at second or third marrow infusions. Both died of infectious complications, 42 and 111 days after transplant.

Adult↗
PubMed1985

Marrow transplantation: the Seattle experience.

Marrow transplantation is effective treatment for a number of hematological diseases in patients under the age of 50 who have an HLA-identical sibling donor. It is successful in the treatment of aplastic anemia with 70-85% long-term survival. It offers 10-30% apparent cures for patients with acute leukemia who have relapsed at least once, and for those with chronic myelocytic leukemia in blast crisis. Although still somewhat controversial, it appears to be the treatment of choice for patients with acute nonlymphoblastic leukemia in first chemotherapy induced remission, and for those with chronic myelogenous leukemia in the chronic phase since approximately 50-60% of these patients experience long-term, disease-free survival. Patients with acute lymphoblastic leukemia grafted in second or subsequent remission may expect a 30% "cure" of their disease. Marrow grafting is the only effective treatment for many patients with inherited immunologic deficiencies and certain genetic storage diseases. Cures of congenital Fanconi's anemia, Blackfan-Diamond anemia, osteopetrosis, paroxysmal nocturnal hemoglobinuria and thalassemia major have been achieved. Marrow transplantation is being explored for the therapy of patients with lymphoma, Hodgkin's disease, preleukemia, multiple myeloma, hairy cell leukemia, small cell lung cancer, testicular cancer, ovarian cancer and neuroblastoma. Marrow transplantation has been limited by the fact that many patients do not have HLA-identical siblings and very few have monozygotic twins. More recently, marrow transplants from HLA-nonidentical family members and even from unrelated donors have been successfully explored.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Aplastic↗