Marrow transplantation for acute nonlymphoblastic leukemic in first remission using fractionated or single-dose irradiation.
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Acute Disease↗
Biomedical subjects
R Storb
Publications and source records attributed to R Storb.
Marrow grafts between phenotypically DLA-identical and haploidentical unrelated dogs: additional antigens controlling engraftment are not detected by cell-mediated lympholysis.
Bone marrow transplants with low marrow cell doses (less than or equal to 4 x 10(8) cells/kg) from unrelated donors were carried out in 16 dogs conditioned with 9 Gy (900 rad) of total body irradiation. No immunosuppression was given after grafting. Eleven donor-recipient pairs were phenotypically identical (group 1) for the known antigens of the canine major histocompatibility complex (DLA) and in five the donor was homozygous and the recipient heterozygous for DLA (group 2), as determined by serological histocompatibility typing and mixed leukocyte cultures including homozygous cell typing. In addition, lymphocytes from donors and recipients in group 1 were mutually nonreactive in cell-mediated lympholysis; lymphocytes from recipients in group 2 were not cytotoxic against donor cells. Eight dogs rejected their grafts and eight showed sustained engraftment; of these, four died from graft-versus-host disease. The incidence of rejection was higher than in DLA-identical littermates but lower than in DLA-nonidentical unrelated or littermate dogs. These results indicate that antigens different from the recognized alleles at DLA are involved in the control of engraftment. These antigens most likely represent the expression of unrecognized differences within DLA or are coded for by a locus different from but linked to DLA-A, B, C or D; they are not recognized in the cell-mediated lympholysis assay.
Animals↗
Thymus transplantation after allogeneic bone marrow graft to prevent chronic graft-versus-host disease in humans.
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Acute Disease↗
Engraftment of DLA-nonidentical unrelated canine marrow after high-dose fractionated total body irradiation.
Marrow transplants were carried out between unrelated DLA-nonidentical dogs. Recipients were conditioned for transplantation by total body irradiation (TBI) given eigher as a single dose of 9 Gy (900 rad) or fractionated in three increments of 6 Gy (600 rad) each at intervals of 48 hr. All recipients received marrow, less than or equal to 4 x 10(8) cells/kg, and no buffy coat cells. No immunosuppression was given after grafting. All 10 dogs given single dose total body irradiation failed to show engraftment and died with marrow aplasia and infectious complications (median survival 12 days). In contrast, all 10 dogs given fractionated TBI had sustained engraftment and died with graft-versus-host disease (GVHD) and infectious complications (median survival 12.5 days). None of the dogs died from radiation-induced gastroenteritis. In conclusion, resistance to DLA-nonidentical unrelated marrow grafts can be abrogated by high-dose TBI. This technique may allow hemopoietic engraftment even after i vitro manipulation of the marrow such as lymphocyte depletion by cell separation or treatment with anti-T cell antisera.
Animals↗
A monoclonal antibody (DT-2) recognizing canine T lymphocytes.
A murine monoclonal antibody (DT-2) is described which has been raised against canine thymocytes. DT-2 activates complement and is reactive with most canine thymocytes, peripheral blood T cells, thoracic duct lymphocytes, bronchoalveolar lymphocytes, and T chronic lymphatic leukemia cells. The antibody is nonreactive with surface immunoglobulin-positive blood lymphocytes, monocytes, bronchoalveolar macrophages, null acute lymphatic leukemia cells, granulocytes, erythrocytes, and platelets. In mixed lymphocyte cultures DT-2 and complement eliminate the responding but not the stimulating cell population. Mitogen stimulation (phytohemagglutinin, concanavalin A) experiments revealed that the responding cell affected by DT-2 is of lymphoid and not of monocyte/macrophage origin. All our data suggest that DT-2 is an antibody reacting specifically with canine T cells.
Animals↗
Cyclosporin A and methotrexate in canine marrow transplantation: engraftment, graft-versus-host disease, and induction of intolerance.
We examined the effect of methotrexate (MTX) and cyclosporin A (Cy A) on engraftment, graft-versus-host disease (GVHD), and the induction of tolerance in dogs prepared for marrow transplantation by 9 Gy of total body irradiation and grafted with bone marrow and buffy coat cells. Nineteen dogs were given grafts from DLA-identical littermates followed by immunosuppression with Cy A for 25 or 100 days. All had sustained engraftment, and 12 became healthy long-term chimeras. Sixty dogs were given grafts from DLA-nonidentical unrelated donors. Among nine given MTX only postgrafting, one rejected the graft nd eight died with GVHD. Among 18 dogs given Cy A only postgrafting, eight failed to achieve engraftment, seven died of various causes, and three died with GVHD. Thirty-four dogs were given both MTX and Cy A in various regimens postgrafting. The only long-term survivors were 4 of 10 dogs given MTX on days 1, 3, 6, and 11 and Cy A from days 0 through 100. Two have chronic GVHD. We conclude that Cy A can induce graft-host tolerance across minor, but not major, histocompatibility differences. The combination of MTX early after transplantation with Cy A prevents failure of engraftment of histoincompatible marrow and some recipients become long-term survivors.
Alkaline Phosphatase↗
Immunological studies in patients with aplastic anemia who rejected marrow grafts from HLA-identical sibling donors.
Marrow graft rejection after transplantation from an HLA-identical sibling for the treatment of aplastic anemia has an immunological basis in most cases. We previously studied the post-transplantation sera of 20 consecutive patients using the chromium release assays of complement-dependent cytotoxicity (CDC) and/or antibody-dependent cell-mediated cytotoxicity (ADCC). Reactivity against peripheral blood mononuclear cells of the marrow donors was found which was associated with graft rejection. Sera of 17 consecutive patients who rejected their grafts have now been studied. Donor cells susceptible to cytotoxicity in both the CDC and ADCC assays were composed of both adherent and nonadherent cells not forming spontaneous rosettes with sheep red blood cells. Absorption studies demonstrated that the reactivities were mediated by antibody, and inhibition studies with 2-mercaptoethanol indicated that the active component was IgM.
Absorption↗
Bone marrow transplantation in the Wiskott-Aldrich syndrome. Complete hematological and immunological reconstitution.
A 21-month-old boy with the Wiskott-Aldrich syndrome conditioned with cyclophosphamide and dimethyl myleran received bone marrow from an HLA-matched sibling. Complete hematological chimerism was achieved. During the first 3 months after transplantation, in vitro B cell function, measured by a direct plaque assay, was abnormal, T cell helper activity impaired, and suppressor T cell function was excessive. These abnormalities resolved gradually over 16 months. Antibody responses to the T-dependent antigen, bacteriophage phi X174, were initially low, then became normal; antibody responses to keyhole limpet hemocyanin (KLH) and to 4 of 12 type-specific pneumococcal polysaccharide antigens were adequate when studied 9 months after transplantation. The clinical response was excellent: the patient has been free of infection, no longer has a bleeding tendency, and has shown normal growth and development.
Antibody Formation↗
Identical twin marrow transplantation in multiple myeloma.
We performed the first successful syngeneic bone marrow transplantation (BM Txp) in a patient with multiple myeloma. The patient and his normal identical twin are 50-year-old physicians. Prior to BM Txp, a partial remission was achieved with 1 year of continuous low dosage melphalan and prednisone therapy. Immediately before BM Txp, high dose cyclophosphamide and total body irradiation were administered in an attempt to eradicate the residual tumor. For 17 months after BM Txp, the patient was asymptomatic and hematologically normal although a low concentration of serum monoclonal IgGK persisted. In the 18th month, recurrence of bone pain and increase in the monoclonal IgG signalled exacerbation of the disease. Chemotherapy was resumed and again produced objective and subjective evidence of response. This study demonstrates the feasibility and potential usefulness of syngeneic BM Txp in myeloma.
Blood Grouping and Crossmatching↗
Alveolar macrophage kinetics and function after interruption of canine marrow function.
To study the kinetics and function of alveolar macrophages after interruption of marrow function, we performed serial bronchoalveolar lavages in dogs. The studies were performed before and after 9.0 to 9.5 Grey total body irradiation and marrow infusion. Monocytes had disappeared from the bloodstream by Day 7 after the irradiation. Alveolar macrophages were significantly decreased at Day 21. At Days 14 and 21 myeloperoxidase-positive alveolar macrophages were also significantly decreased. Beyond Day 30 the number of circulating monocytes, myeloperoxidase-positive and total alveolar macrophages had returned. Sex chromatin stains of alveolar macrophages obtained from a male dog that received female marrow indicated that the repopulating macrophages were of marrow origin. In vitro studies of alveolar macrophage migration and phagocytosis demonstrated increased activities beyond Day 30. These studies suggest that in this model the alveolar macrophage is dependent on the bone marrow for support and that the alveolar macrophage depletion may impair lung defense mechanisms.
Animals↗
Immediate and delayed neurotoxicity after mechlorethamine preparation for bone marrow transplantation.
Twenty-four patients, including two with aplastic anemia and 22 with malignancy, underwent marrow transplantation after preparation with mechlorethamine, 0.3 to 2.0 mg/kg body weight. Fourteen of the 21 neurologically evaluable recipients developed immediate neurotoxicity a median of 4 days after treatment (range, 0 to 34 days). Confusion and disorientation were observed in six patients, headache in six, hallucinations n four, lethargy in four, tremors in three, paraplegia in one, seizure in one, and vertigo in one. Whereas acute symptoms cleared in 11 patients, three remained symptomatic until death. Twelve evaluable patients survived more than 60 days; all six with previous acute toxicity subsequently developed delayed onset of new neurologic findings (personality change, confusion, seizure, diplopia, or dementia) a median of 169 days (range, 70 to 248 days) after treatment. Cerebrospinal fluid analysis was usually normal but cerebral computed tomographic scans showed ventricular enlargement and electroencephalograms showed diffuse slowing. Postmortem histologic examination of brain showed neuronal degenerative changes with increased vascularity, gliosis, and perivascular fibrosis. Neurotoxicity appeared to increase with age and mechlorethamine dose and was commoner in patients given additional procarbazine or cyclophosphamide.
Adolescent↗
Enhancement of human ADCC with interferon.
We have studied the ability of a purified preparation of leucocyte interferon (IF) to augment human antibody-dependent cell-mediated cytotoxicity (ADCC). The IF preparation was added to cultures of the ADCC assay consisting of peripheral blood mononuclear target cells, a sensitizing human antiserum specific for the HLA antigens expressed on the target cells, and effector cells obtained from the peripheral blood of healthy human subjects. Increased cytolysis was found at each of four effector to target cell ratios but could be demonstrated only at concentrations of the sensitizing antiserum of 2.5% and lower. Removal of monocytes from the effector cell population did not decrease the level of cytotoxicity, and isolated monocytes were unreactive, suggesting that K cells (the subpopulation of lymphocytes mediating ADCC) were susceptible to augmentation. Since it is widely accepted that IF can augment spontaneous cytotoxicity mediated by natural killer (NK) cells, our results provide further evidence that human NK and K cells are the same or similar subpopulations or that the mechanisms regulating the activities of these cells are similar. Furthermore, our findings suggest that IF treatment can improve the discriminatory power of the ADCC assay in detecting transfusion or transplantation related immunity.
Antibody-Dependent Cell Cytotoxicity↗
T-cell subpopulations identified by monoclonal antibodies after human marrow transplantation. I. Helper-inducer and cytotoxic-suppressor subsets.
Peripheral blood helper-inducer and cytotoxic-suppressor T-cell subpopulations in patients receiving marrow transplants for the treatment of acute leukemia or severe aplastic anemia were quantitated on the fluorescence-activated cell sorter (FACS) using the monoclonal antibodies OKT4 and OKT8, respectively. The relative (percent) and absolute number of OKT4+ cells were severely and persistently depleted for up to 2.7 yr posttransplant. In contrast, the percent and absolute number of OKT8+ cells began to recover within the first 60 days of transplant and subsequently remained at normal or high levels for periods of up to 7.3 yr. There was no significant difference in percent or absolute numbers of OKT8+ cells for patients with or without acute graft-versus-host disease (GVHD). The reversal of the normal OKT4:OKT8 ratio (2:1) occurred regardless of whether the recipient was given an allogeneic, syngeneic, or autologous transplant and regardless of whether or not acute or chronic GVHD developed. The reversed ratio was due in the first 3 mo posttransplant to low numbers of OKT4+ cells and later to a combination of low numbers of OKT4+ and high numbers of OKT8+ cells. Normalization and then an increase in the number of OKT8+ cells correlated with increasing time posttransplant and not with resolution of acute GVHD.
Adult↗
The regulation of Ig synthesis after marrow transplantation. IV. T4 and T8 subset function in patients with chronic graft-vs-host disease.
This study compares pokeweed mitogen-activated immunoglobulin synthesis functions of T, T4 T8, and B cells from 13 marrow graft recipients with chronic graft-vs-host disease (GVHD), 10 long-term healthy marrow graft recipients, and 20 normal individuals. T cells expressed helper function (greater than 20% of the control) in eight of 10 long-term healthy patients and in only four of 13 patients with chronic GVHD. T4 cells expressed helper activity in all 10 long-term healthy patients, whereas T4 cells in four of 13 chronic GVHD patients did not express helper activity. Chronic GVHD patients had T cells (eight of 13), T4 cells (four of 13), and T8 cells (11 of 13) that suppressed immunoglobulin synthesis by normal T and B cells greater than 50%; radiosensitive and radioresistant suppressors were detected. Three of 10 patients with chronic GVHD and one of the long-term healthy patients had T4 cells that exhibited suppression. T cells from all 20 normal individuals expressed help and none suppressed immunoglobulin production. Altered T, T4, T8, and B cell functions were more frequent in patients with chronic GVHD than in long-term healthy patients or normals. Variable function within a T cell phenotype, variable radiosensitivity of suppressor cells, and higher frequencies of altered function in patients with chronic GVHD suggest there are different maturational stages expressed in each T cell phenotype.
Antibody-Producing Cells↗
Analysis of late infections after human bone marrow transplantation: role of genotypic nonidentity between marrow donor and recipient and of nonspecific suppressor cells in patients with chronic graft-versus-host disease.
Infections occurring 6 mo or later after bone marrow transplantation for severe aplastic anemia or hematologic malignancy were analyzed in 98 long-term survivors. Varicella-zoster (VZ) infections were analyzed separately from all other infections. The factor predisposing most strongly to late VZ infection was genotypic nonidentity for HLA between marrow donor and recipient. There was a suggestion that chronic graft-versus-host disease (GVHD) associated with the presence of nonspecific suppressor cells also predisposed to late VZ infection, while age less than 10 yr was protective against such infections. Chronic GVHD predisposed to late non-VZ infections, but this was not increased by the presence of nonspecific suppressor cells. HLA nonidentify between patient and marrow donor further increased the risk of late non-VZ infections over and above that due to the presence of chronic GVHD. Receipt of a syngeneic transplant appeared protective for late non-VZ infections. These findings suggest that full genotypic identity for HLA between donor and recipient may be required for optimal immune reconstitution after marrow transplantation and may denote a possible biologic role for nonspecific suppressor T cells in humans.
Acute Disease↗
Immunoglobulin production after marrow transplantation. III. The functional heterogeneity of FC-IgG receptor positive and negative T cell subpopulations.
Ten patients with chronic graft-versus-host disease (GVHD) after HLA-identical marrow transplantation were studied between 372 and 1649 days post-transplant for their T cell subset functions in pokeweed mitogen-stimulated immunoglobulin (Ig) synthesis. In vitro Ig synthesis was assessed using an indirect haemolytic plaque assay after 6 days of culture. T cells, TG+ cells (Fc-IgG receptor positive), TG- cells (Fc-IgG receptor negative), and B cell-enriched populations from the patients were co-cultured with normal T and/or B cells. Such cultures in patients with chronic GVHD showed deficient B cell activity (eight of 10); and deficient helper activity in T cells (six of 10), TG+ cells (five of nine), and TG- cells (three of nine). Greater than 50% suppression of Ig synthesis was detected with T cells (four of 10), TG+ cells (three of 10), and TG- cells (three of 10). This study provides evidence for variable regulatory function of Fc receptor T cell subsets in patients with chronic GVHD. The unexpected finding was that TG+ and TG- subpopulations can lack helper activity or actively suppress Ig synthesis.
B-Lymphocytes↗
In vitro regulation of immunoglobulin synthesis after human marrow transplantation. II. Deficient T and non-T lymphocyte function within 3-4 months of allogeneic, syngeneic, or autologous marrow grafting for hematologic malignancy.
Immunoglobulin secretion was studied in 37 patients between 19 and 106 days after allogeneic HLA-identical (30 patients), allogeneic one HLA-haplotype-identical (three patients), syngeneic (three patients), or autologous (one patient) marrow grafting. E rosette-positive (T) and E rosette-negative (non-T) peripheral blood mononuclear cells were cocultured with pokeweed mitogen for 6 days. Polyvalent immunoglobulin secretion was determined by counting plaque forming cells in a reverse hemolytic plaque assay. The number of antibody secreting cells in cocultures of autologous T and non-T lymphocytes was low in 40 of 44 tests conducted on samples from the 37 patients. Mononuclear or non-T cells from 38 of 40 tests failed to produce antibody when cultured with normal helper T cells. T cells from 23 of 37 tests failed to help normal non-T cells secrete antibody. T lymphocytes from 23 of 41 tests suppressed antibody production greater than 80% by normal T and non-T cells. The suppressor cells were radiosensitive in 17 of the 25 tests. The abnormal function of lymphocyte subpopulations in patients during the first 3 mo after syngeneic, allogeneic or autologous marrow grafting was similar regardless of the type of graft or the presence of acute graft versus host disease.
Acute Disease↗
Gynecologic manifestations of chronic graft-versus-host disease.
Gynecologic manifestations of the clinicopathologic syndrome known as graft-versus-host disease seen in 5 patients treated with allogeneic bone transplantation are presented. The clinical symptoms and significant problems found in association with graft-versus-host disease may include extensive sclerosing vaginitis and stricture formation. Treatment and possible preventive therapy are discussed.
Adolescent↗