Search PubMed⌕ Search

Biomedical subjects

K Atkinson

Publications and source records attributed to K Atkinson.

At least 163 records · Page 9Linked to original sources
PubMed1982

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↗
PubMed1982

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↗
PubMed1982

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↗
PubMed1982

Acute and chronic graft-versus-host disease in dogs given hemopoietic grafts from DLA-nonidentical littermates. Two distinct syndromes.

We recognized two distinct clinical and histologic syndromes of acute and chronic graft-versus-host disease (GVHD) in irradiation chimeric dogs given hemopoietic grafts from DLA-nonidentical littermate donors. Clinically acute GVHD developed, with a median onset of 13 days after the transplant, and was characterized by skin erythema, jaundice, diarrhea, and gram-negative infections; the median survival of these dogs was 29.5 days. Chronic GVHD developed a median of 124 days after the transplant and was characterized by generalized skin ulcerations, massive ascites, and gram-positive infections; the median survival of these dogs was 150 days. Chronic GVHD could be distinguished histologically from acute GVHD by epidermal atrophy and dermal fibrosis and by bile duct proliferation, bridging, piecemeal necrosis, and portal fibrosis in the liver. Questions related to GVHD in man can be investigated in this model of acute and chronic GVHD in a large outbred species.

Acute Disease↗
PubMed1982

Lethal effect of the intravenous injection of H-2 alloantigen activated T cells.

T cells of C57BL/6J (B6) mice activated in vitro against the K and D determinants of the H-2d haplotype, and expanded in tissue culture in the presence of interleukin 2, were capable of rapidly killing lethally irradiated BALB/c recipients when injected intravenously. Mice given 10(6), 10(7) and 10(8) such T cells survived 10.5, 8.5 and 0.5 days respectively. Mice given irradiation only survived 10.5 days. Mice given 10(8) B6 T cells activated against all determinants of a third party haplotype (H-2k) survived 8.5 days. Respiratory distress developed within 3 hr of injection in mice given 10(8) T cells activated against the H-2 alloantigens of the recipient haplotype, and at autopsy their lungs showed pulmonary congestion, focal obliteration of the alveolar space and thickening of alveolar interstitial tissue with fibrin, red cell and a mononuclear cell infiltrate. These findings may have relevance to the use of cellular immunotherapy.

Animals↗
PubMed1982

Low serum thymic hormone levels in patients with chronic graft-versus-host disease.

We tested the hypothesis that chronic graft-versus-host disease (GVHD) is due to inadequate thymic function by examining pretransplant serum levels of facteur thymique serique (FTS). Four of five patients with no detectable FTS activity developed chronic GVHD, while one of four with some FTS activity did. Further patient numbers are needed to confirm or reject this hypothesis. We further postulated that chronic GVHD, whatever its cause, involves thymic epithelium as a target organ. When tested 11 mo or more posttransplant, patients with chronic GVHD had lower absolute FTS levels (p less than 0.02) and lower age-corrected levels (p = 0.05) than patients without chronic GHVD. Low values in chronic GVHD were associated with the disease itself and not its therapy. These findings show that thymic epithelial secretory function is impaired in chronic GVHD, and this may in part be responsible for the immunodeficiency characteristic of these patients.

Adolescent↗
PubMed1982

Cyclosporin-A abrogates transfusion-induced sensitization and prevents marrow graft rejection in DLA-identical canine littermates.

Previous studies had shown that marrow graft rejection generally did not occur in untransfused dogs given 900-rad total body irradiation and hemopoietic grafts from DLA identical littermates (only 1 of 59 rejected), but was seen in all instances after three preceding transfusions of whole blood from the marrow donor on days -24, -17, and -10 before transplantation (19 of 19 rejected). The present study was undertaken to investigate whether immunization by 3 preceding transfusions of whole blood from the DLA-identical littermate marrow donor could be abrogated by administration of the immunosuppressive agent cyclo-sporin-A, 20 mg/kg/day intramuscularly on days -5 to 0. Seven of 10 dogs showed sustained marrow engraftment. 2 failed to engraft, and 1 dog died to early to be evaluated. It was concluded that immunization to non-DLA antigens by preceding whole blood transfusions could be abrogated in most cases by a short-course of cyclosporin-A before total body irradiation and marrow transplantation, resulting in successful and sustained marrow engraftment.

Animals↗
PubMed1981

Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment.

One-hundred fifty-three recipients of HLA-identical sibling marrow transplants for aplastic anemia or hematologic malignancy were injected with bacteriophage phi X174 (phage), pneumococcal polysaccharide antigen (PPA), or keyhole limpet hemocyanin (KLH). Antibody levels were determined several times in the 6 wk after injection. Multiple regression techniques were used to determine what factors played significant roles in the antibody response. The most significant factors were the time elapsed from transplantation, chronic graft-versus-host disease (GVHD), and antithymocyte globulin (ATG) treatment. All patients had low antibody responses to all antigens in the first 180 days from transplant. Beyond 180 days patients without chronic GVHD showed antibody responses indistinguishable from those of normal donors. However, patients with chronic GVHD had the following impairments: (1) primary response to phage, (2) conversion from IgM to IgG in secondary response to phage, (3) secondary response to KLH, and (4) response to PPA. ATG treatment given to patients either prophylactically or therapeutically for acute GVHD was followed by lower primary responses to phage in the first 180 days and poor ability to switch from IgM to IgG antibody in the secondary response beyond 180 days postgrafting. Other factors did not yield additional significant information about ability to predict antibody responses including diagnosis, conditioning regimen, treatment in or out of laminar air flow rooms, transplantation, pretransplant refractoriness of the recipient to platelet transfusions from random donors, donor age or donor sex, and steroid administration for treatment for prevention of GVHD. The data indicate that, given enough time after transplantation, the ability to produce normal antibody function recovers except in those patients experiencing chronic GVHD.

Antibodies↗
PubMed1981

Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression.

Fifty-two of 175 (30%) survivors of allogeneic marrow transplantation developed chronic graft-versus-hose diseases (GVHD). Five with limited chronic GVHD had an indolent clinical course with involvement of only the skin and liver. Forty-seven with extensive chronic GVHD had an unfavorable multiorgan disorder that resembled several autoimmune diseases. Thirteen patients with extensive disease (group I) were not treated and only 2 survive with Karnofsky scores >- 70%. Mortality resulted from infections and morbidity from sica syndrome, pulmonary and hepatic insufficiency, scleroderma-like skin disease, and contractures. Another 13 (group II) received a median of 8 mo prednisone and/or a brief course of antithymocyte globulin, and 3 survive without disability. The other 21 (group III) were treated with a combination of prednisone (1.0 mg/kg/q.o.d.) and either cyclophosphamide, procarbazine, or azathioprine (all 1.5 mg/kg/day) for a median of 13 mo. Combination therapy was well tolerated with only modest myelotoxicity. Fifteen in group III had a good and 4 a fair response to treatment while 2 with no response died. Azathioprine and prednisone was the most effective regimen. All therapy has been discontinued in 12 group III patients: GVHD returned in 5 (including 2 who died in spite of retreatment) while 7 remain free of GVHD for a median of 11 (range 6-30) mo observation. Only I group III survivor is disabled and 16 of the original 21 are alive 2-4 yr after transplant with Karnofsky scores of 70%-100%. Thus, combination immmunosuppression appears to favorably affect and, in some cases, premanently arrest the adverse natural course of extensive chronic GVHD.

Antilymphocyte Serum↗
PubMed1980

Yeast mutant defective in phosphatidylserine synthesis.

Phospholipid biosynthesis in a mutant of Saccharomyces cerevisiae (cho1) which lacks phosphatidylserine (Atkinson, K. D., Jensen, B., Storm, E., Kolat, A. I., Henry, S. A. & Fogel, S. (1980) J. Bacteriol. 141, 558-564) has been examined. The ability of cells of this strain to synthesize phosphatidylserine in vitro in a cell-free system is reduced at least 10-fold, whereas other phospholipid-synthesizing activities are present at normal or slightly elevated levels. While all phospholipid biosynthetic activities, except phosphatidylserine synthesis, can be demonstrated in vitro in the cho1 mutant, the entire pattern of phospholipid synthesis, accumulation, and turnover in vivo is distorted. Phosphatidylinositol synthesis is elevated, as is phosphatidylcholine synthesis. In addition, the turnover of phosphatidylcholine is more rapid in the cho1 mutant. The cho1 mutant appears to use almost exclusively the alternative pathway described by Kennedy and Weiss (1956) J. Biol. Chem. 222, 193-214) for the production of phosphatidylethanolamine and phosphatidylcholine, bypassing phosphatidylserine as an intermediate.

Ethanolamines↗
PubMed1980

Varicella-zoster virus infection after marrow transplantation for aplastic anemia or leukemia.

Nearly one-half of marrow transplant recipients who survive at least 6 months develop varicella-zoster virus (VZV) infection. Of 92 cases studied, 82 occurred within the first 12 months after transplant. Only one patient had recurrent infection. Seventy-seven patients had herpes zoster, 22 with subsequent cutaneous dissemination, and 15 had varicella. The overall mortality rate was 8%, and all deaths occurred within 9 months of transplant. Twenty-six of 32 patients studied had significant rises in VZV antibody during recovery. Among patients with acute leukemia, those with syngeneic transplants had a significantly lower incidence of VZV infection than those with allogeneic transplants. Incidence was slightly, but not significantly, decreased among patients with aplastic anemia. In contrast to other infections, the incidence of VZV infection was not influenced by graft-versus-host disease or predicted by the results of dinitrochlorobenzene skin testing.

Adolescent↗