Correction of congenital bone marrow disorders by allogeneic bone marrow transplantation following preparation with anti-human thymocyte serum and total body irradiation.
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Adolescent↗
Biomedical subjects
R Parkman
Publications and source records attributed to R Parkman.
Correction of infantile agranulocytosis (Kostmann's syndrome) by allogeneic bone marrow transplantation.
Allogeneic bone marrow transplantation has been unsuccessful as therapy for genetically determined bone marrow disorders. In patients prepared for transplantation with drugs alone long-term hematopoietic engraftment is not achieved due to the overgrowth of the infused donor bone marrow cells by residual recipient hematopoietic stem cells. Utilizing a combination of total body irradiation and antihuman thymocyte serum, the successful eradication of the abnormal hematopoietic stem cells of patients with the Wiskott-Aldrich syndrome and now infantile agranulocytosis has been achieved. Following preparation with total body irradiation and antihuman thymocyte serum a 20 month old patient with infantile agranulocytosis has complete donor hematopoietic and lymphoid engraftment one year after a histocompatible allogeneic bone marrow transplant. Prior to transplantation, this patient had no circulating or bone marrow granulocytes; following transplantation he has normal numbers of circulating granulocytes with normal in vivo and in vitro function. This therapeutic result demonstrates that genetic disorders of myeloid function can be corrected by allogeneic bone marrow transplantation following preparation with total body irradiation and antihuman thymocyte serum, and suggests that infantile agranulocytosis is due to an intrinsic defect of the pluripotent hematopoietic stem cell and not to a micro-environmental defect.
Agranulocytosis↗
Increased serum immunoglobulin E levels following allogeneic bone marrow transplantation.
IgE levels were determined before and serially after allogeneic bone marrow transplantation (BMT) in 12 patients. Six patients had aplastic anemia, four leukemia, and one each Wiskott-Aldrich syndrome and infantile agranulocytosis. IgE levels increased sharply (7- to 2,000-fold) in 10 of the 12 as early as 14 days after BMT. They all returned to baseline levels by 60 days. In six of these patients, the rise accompanied clinical and biochemical evidence of acute graft-versus-host disease (GVHD). All of the patients who received rabbit antihuman thymocytic serum (ATS) in preparation for transplantation and were tested for IgE antirabbit serum antibody by radioallergosorbent test (RAST) (n = 6) developed a strongly positive RAST which paralleled their total IgE levels. These high IgE levels detected during the period of acute GVHD may be a manifestation of a transient lack of suppressor T cell activity.
Adolescent↗
Development of a nonthrombogenic collagenous blood-prosthetic interface.
Investigations to develop an implantable assist pump for prolonged circulatory support have been impeded by accumulation of friable thrombus on the prosthetic interface, with subsequent embolization. To circumvent this problem, the textured, fibril surface of a polyurethane pump chamber (mat thickness 430 microns) was inoculated with cultured bovine fetal fibroblasts (labelled with thymidine-14C) prior to animal implantation. The pneumatically actuated device (stroke volume 75 ml), maintained a pulsatile blood flow throughout each study. In 20 calf experiments, extending up to 335 days, 30 X 10(6) fibroblasts (in 50 ml media) derived from a single Holstein fetus were distributed on the urethane surface (360 +/- 50 cells/mm2) by rotation of a sealed device for three hours (12 revolutions/hour). Following connection to the circulation, cell washout was minimal. Resultant biologic linings, examined after animal sacrifice, were densely adherent to the underlying polymer matrix, and varied in thickness from 250 micron-1.5 mm. Microscopically, fibroblasts were identified from the surface to base, accompanied by numerous collagen bundles and abundant ground substance. Amino acid analysis in 10/20 pumps implanted for 31--335 days, revealed 50 +/- 5 Hydroxyproline residues/1000 residues (50% collagen) and scant elastin. Donor fibroblasts were identified by radioautography and karyotyping. Lack of immunologic response in 12 Hereford pump recipients as confirmed by serial fibroblast cytotoxicity assays. In conclusion, an induced collagenous-blood interface permitted prolonged mechanical circulatory support in animals without thromboembolic complications.
Animals↗
Human graft versus host disease.
Human graft versus host disease is composed of 2 distinct clinical entities, acute graft versus host disease and chronic graft versus host disease, which have different pathogenesis. Acute graft versus host disease is produced by the attack of donor immunocompetent T or null lymphocytes against recipient histocompatibility antigens. The null lymphocytes may attack antigens shared by the donor and recipient and are autocytotoxic lymphocytes which can produce acute graft versus host disease in recipients of identical twin transplants. The cessation of acute graft versus host disease occurs when suppressor lymphocytes appear in the recipient's peripheral circulation. Chronic graft versus host disease is produced by immunocompetent lymphocytes that differentiate in the recipient. Its control is unknown. Some patients with chronic graft versus host disease have in vivo activated suppressor lymphocytes which produce a secondary immunoincompetence and an increased susceptibility to bacterial sepsis and death.
Antibody Formation↗
Control of autologous immune complex nephritis. I. Suppression of the disease in the presence of T cell sensitization.
Pretreatment of Lewis and Sprague-Dawley rats with the nephritogenic antigen, Fx1A, in incomplete Freund's adjuvant (IFA) reduced the incidence of autologous immune complex nephritis in rats subsequently challenged with Fx1A in complete Freund's adjuvant (CFA). The suppression was evidenced by a decrease in antibody production, in glomerular deposition of immunoglobulins, and in the incidence of proteinuria, and it was antigen specific. In vitro blastogenesis to Fx1A of lymphocytes from Fx1A-IFA-pretreated animals was normal. Rats pretreated with Fx1A-IFA initially developed a normal antibody response after challenge with Fx1A-CFA, but the response was not sustained. These results indicate that the Fx1A-IFA-induced suppressor mechanism does not inhibit sensitization, but rather modifies specific antibody production.
Animals↗
Development of collagenous linings on impermeable prosthetic surfaces.
In an effort to accelerate development of a biologic lining on the fibrillar surface of a left ventricular assist pump, the blood-contacting interface was covered with bovine fetal fibroblasts immediately prior to implantation into the animal. Selection of these syngeneic cells was based on their demonstrated prolificacy and abundant collagen production. Comparative studies, carried out in 17 Holstein calves, indicated that an adherent, thin, collagenous lining developed on the fibroblast-seeded polyurethane pump chamber in nine animals. Similar implantations of eight non-cell-seeded (control) devices resulted in formation of a predominantly acellular, fibrinous membrane, varying in thickness from 1 to 8 mm. Pump chamber compliance was significantly reduced when the histologic surface exceeded 3 mm in thickness, resulting in impaired filling and an inadequate stroke volume. The use of 14C-thymidine-labeled fibroblasts permitted later identification of the donor cells in the collagenous linings by radioautography. Serial immunologic studies undertaken to detect evidence of rejection in recipient Holstein calves were negative.
Amino Acids↗
Aplastic anemia: lack of inhibitory effect of bone marrow lymphocytes on in vitro granulopoiesis.
Prompted by previous reports that in certain patients with aplastic anemia, cell-mediated autoimmune suppression of myeloid stem cell proliferation may be demonstrable in vitro, we studied the effects of bone marrow lymphocytes from 18 patients with myeloid aplasia on the proliferation of committed granulocytic-monocytic progenitor cells (CFU-C). When assayed in soft agar cultures, marrow suspensions from 10 patients with aplastic anemia contained significantly fewer viable CFU-C than similar cell preparations from control subjects. To deplete marrow cell suspensions of lymphocytes, we employed rabbit anti-human thymocyte serum (ATS), which after multiple adsorptions exhibited marked cytotoxicity for human B and T lymphocytes but had negligible effect on normal CFU-C proliferation. Preincubation of marrow samples from 12 patients with ATS and complement resulted in no inhibition or enhancement of CFU-C growth. In further experiments, marrow cells from 8 patients were incubated with marrow from control subjects prior to CFU-C culture. No suppression of donor CFU-C proliferation was observed in any of these studies, and in 4 cocultures, mixture of the 2 marrow suspensions resulted in stimulation of CFU-C growth. Using these assays, we detected no evidence of cell-mediated inhibition of CFU-C proliferation in any of the 18 patients that we evaluated. Our data support the conclusion that in the majority of patients with aplastic anemia, an absolute deficiency of hemopoietic stem cells is present within the marrow that does not appear to be effected or sustained by suppressor lymphocytes. Whether the reduction of viable stem cells is the cause or the consequence of the process that leads to marrow failure remains unknown.
Anemia, Aplastic↗
Acute graft-versus-host disease in recipients of bone-marrow transplants from identical twin donors.
Three patients with acute leukaemia received bone-marrow from identical twin donors after pre-transplant preparation with cyclophosphamide, cytosine arabinoside, and total body irradiation. Later clinical and microscopic changes in all three patients suggested cutaneous acute graft-versus host disease. In two of the recipients thrombolytic thrombocytopenia developed during the seventh week after transplantation, and platelet half-life was reduced to 9 h in one recipient (normal 3--4 days). It is suggested that acute graft-versus-host disease in bone-marrow recipients sometimes may result from an imbalance between autoreactive lymphocytes and lymphocytes which suppress their effect and not always from genetically determined histocompatibility differences between donor and recipient.
Acute Disease↗
Aberrations of suppressor T cells in human graft-versus-host disease.
To determine whether imbalances in immunoregulatory T-cell subsets exist in patients with graft-versus-host disease, we analyzed T cells in three patients with acute and in six patients with chronic graft-versus-host disease after bone-marrow transplantation. The normal human peripheral-blood T-cell compartment is composed of 80 per cent TH2-and 20 per cent TH2+ T cells, and defined by reactivity with subset-specific heteroantiserums. Human suppressor cells are TH2+, whereas helper cells are TH2-. Patients with acute and chronic graft-versus-host disease had abnormalities in these populations, and their T cells frequently bore la-like antigens. Patients with acute disease lacked TH2+ cells, and the reappearance of this subset preceded the cessation of disease activity. Chronic disease, in contrast, was more heterogeneous. Suppressor cells were lacking in two patients but increased in the other four. Two of these four patients had TH2+, la+ T cells, suggesting in vivo activation of suppressor cells. Studies showing that these TH2+, la+ cells actively suppressed the in vitro immune response support this hypothesis and suggest that the immunoregulatory cells may profoundly affect the overall immune response.
Acute Disease↗
Successful bone marrow transplantation in sensitized recipients.
Fourteen patients with aplastic anemia and one with the Wiskott-Aldrich syndrome who were specifically sensitized against their donors were successfully engrafted with bone marrow from those donors. Sensitivity was detected in antibody-independent and antibody-dependent cell-mediated lysis assays. In order to erase this immunity to non-MHR familial transplantation antigens, multiagent immunosuppression with cyclophosphamide, procarbazine, and whole rabbit antithymocyte serum (ATS) was used. The data suggest that ATS was largely responsible for abrogation of this sensitivity and indicate that immunity does not represent a barrier to successful transplantation.
Anemia, Aplastic↗
Serum IgE levels following allogeneic bone marrow transplantation in man.
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Adolescent↗
Complete correction of the Wiskott-Aldrich syndrome by allogeneic bone-marrow transplantation.
Two patients with the Wiskott-Aldrich syndrome had complete donor lymphoid and hematopoietic engraftment after successful allogeneic bone-marrow transplantation. One patient had had only a temporary donor T-lymphocyte graft after a previous transplantation, for which he had been prepared with cytarabine and cyclophosphamide; the patient's own T lymphocytes returned six months later. A repeat transplant, for which the patient was prepared with anti-human thymocyte serum, total-body irradiation and procarbazine, resulted in complete donor engraftment. The second patient underwent a successful transplantation after similar preparation, except that procarbazine was omitted. At 11 and five months after transplantation both had normal hematopoiesis and no evidence of graft-versus-host disease. This treatment of the Wiskott-Aldrich syndrome may be a model for the correction of other genetically determined immune and hematologic bone-marrow disorders.
Antilymphocyte Serum↗
Transfer factor treatment of chronic mucocutaneous candidiasis: requirement for donor reactivity to candida antigen.
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Amphotericin B↗
Proliferative and interferon responses by peripheral blood mononuclear cells after bone marrow transplantation in humans.
The capacity of peripheral blood mononuclear cells from bone marrow transplant recipients to proliferate and produce interferon in response to mitogens and specific antigens was tested. Proliferation in response to phytohemagglutinin or pokeweed mitogen occurred in cells from more than 90% of the recipients, and interferon was present in 60 to 70% of the supernatants from these cultures, even when tested as soon as 8 weeks after transplantation. Proliferation in response to bacterial antigens was infrequent, and interferon release was not detected. In the early post-transplantation period (less than 13 weeks), cells from only two of four cytomegalovirus (CMV) antibody-positive patients proliferated normally in response to CMV antigen and interferon release was detected only once. In the late post-transplantation period (more than 13 weeks), in only two of five instances did cells proliferating in response to CMV antigen release interferon. The response to CMV antigen of mononuclear cells from many transplant recipients differs from that of cells from normal controls.
Antigens, Viral↗
The control of autoreactivity. I. Lack of autoreactivity in murine spleens is due to concomitant presence of suppressor and autocytotoxic lymphocytes.
To determine if autocytotoxic lymphocytes were naturally occurring in murine spleens, C57BL/6 spleen cells were fractionated on discontinuous BSA gradients. Autocytotoxicity was assessed in vitro (cytotoxicity of C57BL/6 fibroblasts) and in vivo (splenomegaly and popliteal node enlargement in C57BL/6 mice). A medium density subpopulation of lymphocytes was shown to be autocytotoxic and to be similar to autoreactive lymphocytes produced by the in vitro "sensitization" of splenic lymphocytes on syngeneic fibroblasts monolayers. The naturally occurring autocytotoxic lymphocytes express no detectable theta antigen, did not adhere to nylon, but did have an Fc receptor. In recombination experiments, BSA-fractionated lymphocytes were incubated with autocytotoxic and "sensitized" lymphocytes. A light density subpopulation was shown to suppress both autoreactive lymphocyte subpopulations at a 1:50 ratio. The suppressor cells were nylon nonadherent T lymphocytes. The lack of autoreactivity of unfractionated murine spleen cells is due to the concomitant presence of autocytotoxic and suppressor lymphocytes. If suppressor lymphocytes are selectively removed in vitro, the reactivity of autocytotoxic lymphocytes can be detected.
Animals↗
Prognostic value of antibody-dependent assays for presensitization in bone marrow transplant recipients.
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Anemia, Aplastic↗
Successful use of multiagent immunosuppression in the bone marrow transplantation of sensitized patients.
Of 23 patients with severe aplastic anemia, 17 were sensitized to histocompatibility antigens of HLA-A, -B, and -D loci-identical potential sibling donors as determined by cell-mediated lysis (CML) assays in vitro. Antibody-dependent sensitization was detected in 3 patients, antibody-independent cellular sensitization in 11, and both in 3. Fourteen sensitized patients were transplanted after initial multiagent immunosuppression consisting of rabbit anti-human thymocyte serum, procarbazine, and cyclophosphamide, eleven with a CML-positive donor and three with a CML-negative donor. Engraftment was achieved in each of 13 patients who were evaluable, and only 2 ultimately rejected their marrow grafts, 1 with subsequent return of his own marrow function. Five patients without evidence in vitro of sensitization were transplanted after immunosuppression with cyclophosphamide alone; none of these rejected their grafts. These studies show that sensitized bone marrow transplant recipients can be successfully transplanted after optimal donor selection and multiagent immunosuppression.
Adolescent↗