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Biomedical subjects

S Slavin

Publications and source records attributed to S Slavin.

At least 343 records · Page 19Linked to original sources
PubMed1982

Fractionated total lymphoid irradiation as preparative immunosuppression in high risk renal transplantation: clinical and immunological studies.

Twenty-two patients at high risk to reject renal allografts have been treated with fractionated total lymphoid irradiation (FTLI) prior to transplantation of primary (2), secondary (16) or teritary (4) renal allografts. All patients undergoing retransplantation had rapidly rejected previous grafts. At 24 months following transplantation, 72% of grafts were functioning in the TLI group compared with a 38% graft function in an historical control group of recipients receiving secondary or tertiary grafts and treated with conventional immunosuppression. Important variables in determining success of transplantation following fractionated TLI include the dose of TLI, the interval from radiation to transplantation, and maintenance, post-transplant immunosuppressive therapy. Optimal results were achieved with 2500 rads delivered in 100 rad fractions followed by transplantation within two weeks, and a tapering prednisone schedule and maintenance azathioprine post-transplantation. Seventeen patients had significant complications of the radiation treatment and there was one death, prior to transplantation, associated with pneumonitis. In vitro assessment of immune function demonstrated marked peripheral T cell depletion and loss of in vitro responsiveness to mitogen and allogeneic stimulation following FTLI. The administration of donor bone marrow at the time of transplantation did not produce chimerism. The results suggest that when properly utilized FTLI can produce effective adjunctive immunosuppression for clinical transplantation.

Adolescent↗
PubMed1982

Transplantation of islet cells across major histocompatibility barriers after total lymphoid irradiation and infusion of allogeneic bone marrow cells.

Diabetic Lewis rats (AgB1/L) were evaluated as recipients of allogeneic Wistar-Furth (AgB2/2) isolated adult islets without the use of standard recipient immunosuppression. One group was treated with fractionated total lymphoid irradiation (TLI) and Wistar-Furth bone marrow cell reconstitution to proven chimerism prior to islet transplantation. This group returned to a prediabetic state following Wistar-Furth islet transplantation without any evidence of rejection for 100 days posttransplant. A second group of Lewis rats received only TLI without bone marrow treatment. They gave a varying result following islet transplantation with one recipient showing evidence of prolonged islet survival. A third chimeric control group did not receive isolated islets and did not alter their diabetic state. A fourth group was not given TLI nor donor bone marrow cells and uniformly rejected their allogeneic islets by 7 days. Thus, allogeneic adult islets will survive across major rat histocompatibility barriers using TLI and donor bone marrow chimerism as the only form of immunosuppression.

Animals↗
PubMed1982

Hemopoietic activity in bone marrow chimeras prepared with total lymphoid irradiation (TLI).

The hemopoietic status was examined in the blood, bone marrow and spleen of (BALB/c X C57BL/6)F1 hybrid mice treated with fractionated total lymphoid irradiation (TLI), with or without reconstitution with 30 X 10(6) syngeneic or parental C57BL/6 marrow cells. Colony forming units of pluripotent (CFUS) and granuloid committed stem cells (CFUC) were assayed in non-irradiated (femur) and irradiated bone marrow (humerus), and in spleen 9, 18, 73 and 109 days following TLI. Recovery of CFUS and CFUC was nearly complete as early as day 18, and fully recovered on day 73 in endogenously as well as exogenously (syngeneic and semiallogeneic) reconstituted mice. Mice transplanted with C57BL/6 bone marrow exhibited a 10-fold increase of CFUC in the spleen on day 9 and maintained a 4-fold increase of CFUC on day 109, with normal CFUC in shielded, and near normal CFUC in irradiated bones. In contrast, the number of CFUS in the irradiated humerus was below 10% of all controls on days 18-73 and below 30% on day 109. Also, the number of CFUS in the spleen was very much reduced at days 73-109. Unirradiated femora contained normal CFUC and only mildly depressed CFUS. The data suggest that repopulation of bone marrow is adequate although somewhat less efficient in irradiated as compared to shielded bones, whether or not exogenous marrow is transplanted. Semiallogeneic chimeras (C57BL/6 leads to F1) show low CFUS relative to high CFUC levels, particularly in irradiated organs (spleen and humerus). This may suggest an advantage, from a hemapoietic standpoint, to selective irradiation of lymphoid tissues, rather than the less selective wide fields that overlap marrow containing bones.

Animals↗
PubMed1982

Long-term enzyme replacement therapy in beta-glucuronidase--deficient mice by allogeneic bone marrow transplantation.

Enzyme replacement therapy was successfully accomplished in beta-Glu-deficient C3H/HeJ mice after transplantation of BM cells obtained from normal BALB/c donors. Marrow recipients were prepared for transplantation by fractionated TLI. Enzyme activity increased from 20.5 +/- 7.0 nmol/mg of protein per hour to 180 +/- 30.2 in the liver (p less than 0.001) and from 8.2 +/- 2.0 to 17.5 +/- 5.0 nmol/ml/hr in the plasma (p less than 0.05) at 50 days after marrow infusion. Normal enzyme activity was maintained in treated mice for at least 100 days after marrow transplantation, as documented by repeated liver biopsies and examination of plasma samples. The marrow donors and the recipients were fully histoincompatible. Both immunologic rejection of the marrow allograft and GVHD were prevented by the prior conditioning of the recipients with TLI, resulting in bilateral transplantation tolerance of host vs. graft and graft vs. host. The data suggest that allogeneic BM transplantation may provide a possible therapeutic approach for certain enzyme deficiency syndromes.

Animals↗
PubMed1981

Kidney allograft survival in dogs treated with total lymphoid irradiation.

Total lymphoid irradiation (TLI) is immunosuppressive and, in rodent, can induce a state where transplantation of allogeneic bone marrow results in chimerism and permanent acceptance of organ allografts from the donor strain. We attempted to apply this treatment to a large animal model. Twelve splenectomized dogs were treated with TLI (150 rads per fraction, total dose 1950-3000 rads) before bilateral nephrectomy and renal allotransplantation. Eight dogs received bone marrow from the kidney donor. In 13 untreated control dogs renal allografts functioned (serum creatinine level less than 2.0 mg/dl) for a mean +/- (SE) of 4.7 +/- 0.3 days. In the four TLI treated dogs who did not receive bone marrow the renal allografts functioned for 15-76 days (two dogs died with functioning grafts). In the eight TLI treated dogs who received donor bone marrow, two died immediately after transplantation, two rejected at 3 and 13 days, one died at 13 days with a functioning graft, and two have had the grafts function for longer than 500 days. Chimerism was not detected in the one dog tested. The response of peripheral blood lymphocytes to stimulation with phytohemagglutinin and in mixed lymphocyte culture was suppressed for at least on month after TLI. The results confirm the immunosuppressive effect of TLI. The absence of kidney rejection in two recipients of donor bone marrow show the potential of this approach to induce long-term immunologic unresponsiveness as to an organ allograft, but the outcome is unpredictable and further experiments are needed to define the optimal conditions for administration of TLI and bone marrow to the recipients.

Animals↗
PubMed1981

In-vitro T cell mediated function in patients with active rheumatoid arthritis.

In-vitro synthesis of peripheral blood lymphocytes from patients with rheumatoid arthritis was measured after stimulation with phytohaemagglutinin (PHA) in a short-term, serum-free culture system. Diminished responses were found in 16 out of 17 consecutive patients with active disease. Normal PHA responsiveness was recovered by assaying Ficoll-Hypaque isolated E rosette forming cells in serum-free medium, indicating basically normal T cell function in RA. Preincubation of normal peripheral blood lymphocytes (or isolated E rosette forming cells) with sera obtained from patients with active RA for 30 minutes at 4 degrees C or 37 degrees C blocked PHA responsiveness in 34 out of 43 tests. This suggests that serum blocking factors may be responsible for reduced T cell reactivity in RA.

Arthritis, Rheumatoid↗
PubMed1981

Ultrastructural, cell membrane, and cytogenetic characteristics of B-cell leukemia, a murine model of chronic lymphocytic leukemia.

A murine model of a spontaneous, transplantable BALB/c B-cell leukemia (BCL1) is described. Extreme leukemia and splenomegaly develop in H-2d-compatible recipients of tumor cells. Tumor cells are medium to large lymphocytes that can be transformed into plasmacytoid cells following in vitro stimulation with lipopolysaccharide. Karyotypic analysis of transformed tumor cells reveals 36 chromosomes with several monosomies and 7 markers chromosomes. The ultrastructure of the tumor cells was studied using transmission and scanning electron microscopy. Although the appearance of tumor cells seems normal by morphological criteria, an impaired capping ability was documented using the fluorescein-conjugated concanavalin A-binding test. Impaired capping ability was documented before leukemia was overt as early as 1 to 3 days following inoculation of tumor cells. The B-cell leukemia (BCL1) provides a useful murine model for the study of various aspects of human bone marrow-derived malignant disorders.

Animals↗
PubMed1980

Correction of enzyme deficiency in mice by allogeneic bone marrow transplantation with total lymphoid irradiation.

Enzyme deficiency was corrected in mice after allogeneic bone marrow transplantation with occurrence of graft versus host disease. beta-Glucuronidase-deficient C3H/HeJ mice were treated with total lymphoid irradiation. Normal bone marrow cells (30 X 10(6)) from BALB/c to C3H/HeJ chimeras (>90 percent circulating donor-type cells) without graft versus host disease. beta-Glucuronidase activity increases to normal levels in all chimeras as measured in the liver and in the plasma. Activity was maintained throughout an observation period of 7 months.

Animals↗
PubMed1980

Cell mediated autoimmune granulocytopenia in a case of Felty's syndrome.

A variety of mechanisms have been demonstrated or suggested to explain the neutropenia that accompanies Felty's syndrome. This case report presents with Felty's syndrome with recurrent infections with initially had a clinical response to splenectomy. Eleven years later profound neutropenia recurred. In-vitro evidence for cell mediated autosensitisation of peripheral blood lymphocytes to autologous bone marrow cells was found. The cellular abnormalities improved after high-dose corticosteroids but not lithium. However, there did not appear to be a reduction in the incidence of clinical infections. The finding suggests that granulocytopenia in some patients with Felty's syndrome may be an autoimmune phenomenon.

Agranulocytosis↗
PubMed1980

Immunosuppression and organ transplantation tolerance using total lymphoid irradiation.

Total lymphoid irradiation (TLI) is a method which delivers irradiation daily in fractionated doses (200 rads) to lymphoid organs while shielding bones, lungs, and the majority of the gastrointestinal tract. TLI is lymphocytopenic in mice, rats, dogs, and humans, and both T cells and B cells are eliminated from the circulation. During the recovery phase in mice, B cells appear before Thy 1.2-bearing T cells, and TL-positive T cells are abundant in the spleen and lymph nodes. These T cells exhibit nonspecific suppressive activity on antibody production and cell-mediated immune responses. TLI permits establishment of specific and long-lasting tolerance to alloantigens. Permanent acceptance of allogeneic bone marrow cells without graft-versus-host disease was achieved in rats and dogs across major histocompatibility barriers. Recipients were tolerant to allografts of skin, hearts, and kidney from animals syngeneic to marrow donors or to organs from the marrow donor. This approach may be suitable for pancreas transplantation in diabetes.

Animals↗