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S Slavin

Publications and source records attributed to S Slavin.

At least 109 records · Page 6Linked to original sources
PubMed1984

Demonstration and characterization of virus released by murine B cell leukemia cells (BCL1).

LPS-stimulated leukemia cells derived from BALB/c mice bearing transplantable B-lymphocytic leukemia (BCL1) which arose spontaneously in a female BALB/c mouse, contained viral particles as suggested by electron microscopy as well as by tissue cultures using the XC assay. Some cell free extracts prepared from BCL1 cells were capable of transforming normal B-lymphocytes when inoculated into untreated syngeneic recipients. Cytogenetic analysis of spleen cells obtained from a splenomegalic male mouse neonatally inoculated with cell-free extract indicated that the tumor cells had a male karyotype with 42 chromosomes as compared to 37 chromosomes and a female karyotype in original BCL1 cells, thus excluding the possibility of tumor propagation by transplantation of intact BCL1 cells. These findings suggest viral involvement in the etiology of BCL1.

Animals↗
PubMed1984

Total lymphoid irradiation prevents diabetes mellitus in the Bio-Breeding/Worcester (BB/W) rat.

Total lymphoid irradiation (TLI) at doses of 2200 rads or greater prevented diabetes in susceptible BB/W rats. Two of 29 (7%) treated rats became diabetic compared with 23 of 39 (59%) controls (P less than 0.001). TLI did not, however, prevent insulitis or thyroiditis in nondiabetic rats, nor did it restore the depressed concanavalin-A responsiveness of BB rat lymphocytes. T-lymphocyte subset proportions were the same in both groups. TLI was associated with significant radiation-related mortality, and nondiabetic TLI-treated rats weighed significantly less than controls. We conclude that TLI is effective in the prevention of BB rat diabetes. However, TLI fails to correct the subclinical immunologic abnormalities of the model and is associated with significant morbidity.

Animals↗
PubMed1984

Suppression of cell-mediated immune responses after total lymphoid irradiation (TLI). I. Characterization of suppressor cells of the mixed lymphocyte reaction.

Total lymphoid irradiation (TLI) was administered to (BALB/c X C57BL/6)F1 mice in eight daily doses of 200 rad (total 1600 rad). Spleen cells isolated from mice after treatment with TLI do not respond to alloantigens in vitro in a one-way mixed lymphocyte reaction (MLR), but normal reactivity recovers after approximately 2 mo. Radioresistant, antigen-nonspecific suppressor cells are documented in the spleens of TLI-treated mice immediately after radiotherapy, but suppressive capacity gradually disappears within 30 days. After TLI, the spleen is repopulated with large cells, the proportion of which is greatest at a time when theta-bearing cells are still depleted. Radioresistant suppression is mediated predominantly by the large cell subset and is thymus independent. Suppressor function can be abolished by lethal physicochemical procedures including formaldehyde fixation, multiple freeze-thawing, and heating to 56 degrees C, and it cannot be conferred by supernatants of TLI-suppressed MLR suspensions. Suppression cannot be overcome by adding various cell factors including T cell growth factor (TCGF) and lymphocyte-activating factor (LAF), nor is it affected by a prostaglandin inhibitor. Equally potent radioresistant suppressive activity is documented by co-culturing cells derived from other sources enriched in large, immature hematopoietic cells, including fetal liver cells and bone marrow cells obtained from normal and congenitally athymic mice. The presence of a large cell population and MLR suppressor function is also documented in the spleens of mice treated with single dose or fractionated doses of lethal whole body irradiation, followed by reconstitution with bone marrow cells obtained from normal mice. The data suggest that MLR suppressor cells, which are large, immature and predominantly radioresistant, can be induced after a short and well-tolerated TLI regimen.

Animals↗
PubMed1984

Anti-tumor effects of allogeneic bone marrow transplantation in (NZB X NZW)F1 hybrids with spontaneous lymphosarcoma.

Untreated female (NZB X NZW)F1 hybrid mice (B/W F1) were found to develop lymphosarcoma spontaneously as they aged. Tumor incidence was evaluated in B/W F1 mice immunosuppressed with total lymphoid irradiation (TLI) and in TLI-conditioned B/W F1 mice reconstituted with 3 X 10(7) BALB/c bone marrow (BM) cells. BALB/C leads to B/W F1 chimerism (79 to 89% BALB/c-type cells) was confirmed by typing peripheral blood lymphocytes with specific alloantisera and complement by using a microcytotoxicity assay. Chimeras showed no clinical signs of graft-vs-host disease (GVHD). TLI-treated mice seemed to show a slightly accelerated onset of lymphosarcoma as compared with untreated controls, but the difference was not significant (p = 0.08). BALB/c leads to B/W F1 chimeras reconstituted at 1 to 3 mo of age (25 mice) developed no tumors for an observation period of 18 mo after transplantation. In contrast, tumors developed in 24/130 of age-matched controls, and in 13/57 of TLI-treated nonreconstituted age-matched B/W F1 mice. Tumor incidence in BALB/c leads to B/W F1 chimeras transplanted at an older age (9 to 11 mo) was similar to that observed in age-matched TLI-treated B/W F1 mice and age-matched untreated controls. The data suggests that the high naturally occurring incidence of lymphosarcoma could be reversed by reconstituting TLI-treated mice with BM cells (p = 0.027). Thus, allogeneic BM transplantation may exert potent graft-vs-tumor effects (GVT) when tumor susceptible hosts are reconstituted at an early age, whereas GVT is relatively ineffective at an advanced age, which probably correlates with an advanced stage of tumor development. Allogeneic BM transplantation should be additionally explored as a potential clinical tool for eradication of certain solid tumors in adjunct to high-dose radiochemotherapy, inasmuch as GVT seems to be independent of GVHD.

Aging↗
PubMed1983

Successful treatment of autoimmune manifestations in MRL/l and MRL/n mice using total lymphoid irradiation (TLI).

The autoimmune manifestations of MRL-+/+ (MRL/n) and MRL/Mp-lpr/lpr (MRL/l) murine models of systemic lupus erythematosus (SLE) were successfully reversed following total lymphoid irradiation (TLI) therapy consisting of 8-12 daily fractions of 200 rad. Following radiotherapy the characteristic lymphadenopathy of MRL/l disappeared, proteinuria was 334 mg% compared to a peak of 2272 mg% in untreated controls, and the median survival time was prolonged to 423 days compared to 214 days in untreated mice. The albuminuria of TLI-treated MRL/n mice was 194 mg% compared to 1180 mg% in untreated controls. The survival of treated MRL/n mice was prolonged to a median of 389 as compared to 190 days in untreated controls. The effect of TLI on antiDNA antibodies in both MRL/l and MRL/n was less remarkable. However, the antiDNA activity reached normal levels in most long-living mice. The most impressive finding was complete reversal and/or prevention of the SLE-like glomerulonephritis in MRL/l mice as documented by light and electron microscopy. Immunomanipulation with TLI should be further evaluated as a possible treatment modality in intractable human autoimmune disorders.

Animals↗
PubMed1983

Resistance of T suppressor cells to cyclophosphamide administration in total-lymphoid-irradiated mice.

The effect of administration of cyclophosphamide (Cy) on the susceptibility of mice to tolerance induction and its influence on the rate of induced T suppressor cells in antigen-specific and nonspecific systems was assessed using mice that had undergone total lymphoid irradiation (TLI). Tolerance to bovine serum albumin (BSA) was induced in adult mice conditioned by a short course of fractionated total lymphoid irradiation with an injection of nondeaggregated BSA; Cy was administered upon termination of TLI, two days prior to administration of the tolerizing antigen. Susceptibility to tolerance induction and rate of induced T suppressor cells were assessed one month later. Cy-treated TLI mice and mice treated with TLI alone did not respond to a challenge with DNP-BSA in complete Freund's adjuvant, whereas a good response was obtained to an unrelated protein antigen. The induced T suppressor cell rate was measured by inhibition of a secondary anti DNP-BSA response in an adoptive transfer system. The rate of non-antigen-specific T suppressor cells was measured by inhibition of the mixed leukocyte reaction with Concanavalin A-induced T suppressor cells obtained from spleen cells of TLI-treated, or Cy-treated mice, or those given both treatments. The results reveal that Cy treatment of TLI-conditioned mice does not reduce the rate of induced of T suppressor cells in antigen-specific and antigen-nonspecific systems.

Animals↗
PubMed1983

Serum transcobalamin levels as an early indicator of bone marrow engraftment following transplantation.

Three B12 binding proteins, the transcobalamins TCI, TCII and TCIII, were determined serially in the serum of five patients who underwent bone marrow transplantation. The increase in TCII, followed by the increase in TCI, proved to be an early indicator of bone marrow regeneration, reaching a peak of up to twice its normal levels at least 5 d prior to the rise of the peripheral white blood cell count.

Adolescent↗
PubMed1983

Regulation of the immune response in experimental models of autoimmune disorders. II. Induction of suppressor cells of the mixed lymphocyte culture in adult (NZB x NZW)F1 mice using total lymphoid irradiation.

Kinetic studies were done on mixed lymphocyte reaction suppressor cells generated in female (NZB x NZW)F1 hybrid mice (B/WF1) treated with total lymphoid irradiation (TLI) and in stable BALB/c leads to B/WF1 bone marrow chimeras prepared with TLI (8 daily fractions of 200 rads followed by either whole body irradiation 400 rads (WBI) or intravenous cyclophosphamide (CY) 100--200 mg/kg). All chimeras maintained intact BALB/c skin grafts (greater than 500 days) and showed no signs of graft vs host disease (GVHD). Radioresistant alloantigen-nonspecific suppressor cells were apparent in the spleen immediately following TLI (78--88% suppression of 3H-thymidine incorporation by co-cultured spleen cells using unrelated stimulator and responder cells in one way MLR). The suppressive capacity was of a relatively short duration since suppression became inapparent within 15--30 days following TLI. Nonspecific radioresistant suppressor cells were maintained in stable BALB/c leads to B/WF1 chimeras for longer periods of time (7 months in chimeras prepared with TLI and CY and 11 months of chimeras prepared with TLI and WBI). On the other hand, specific suppressor cells blocking host type (B/WF1 chimeras. The data suggest that the impaired suppressive immunoregulatory functions of B/WF1 mice can be corrected by normal stem cells even though maturation occurs in the B/WF1 lymphoid milieu.

Animals↗
PubMed1983

A partial characterization of suppressor cells in the spleens of mice conditioned with fractionated total lymphoid irradiation (TLI).

Total lymphoid irradiation (TLI) is a highly effective modality for inducing immunosuppression and transplantation tolerance. The cellular basis for this immunosuppression is not clear, although T cells have been implicated. To study further the effect of TLI on the immune system, we have examined the B cells and suppressor cells in the spleens from TLI-conditioned mice. Our results indicate that after TLI, the spleen is rapidly repopulated with many large, immature cells. The probable source of these cells is the shielded bone marrow (BM). The B cells from TLI-conditioned mice are transiently immature and hyporesponsive in vitro to a T-independent antigen. Spleen cells from TLI-conditioned mice nonspecifically suppress the in vitro T-independent anti-TNP response of normal B cells. The suppressor cells lack both B and T cell markers and adhere to Sephadex G-10. The suppressor cells in spleens from TLI-treated mice bear a number of similarities to those present in normal BM. When normal BM cells were analyzed by indirect immunofluorescence for the presence of the Mac-1 antigen, two populations of suppressor cells could be identified: one was Mac-1+ and the other was Mac-1-. These data are consistent with the possibility that a subpopulation of the suppressor cells found in normal BM and in the spleens from TLI-conditioned mice are immature cells of the monocytic/granulocytic lineage.

Animals↗
PubMed1983

Suppression and elimination of BCL1 leukemia by allogeneic bone marrow transplantation.

Mice carrying the B cell leukemia (BCL1)+ were successfully treated by total lymphoid irradiation (TLI), cyclophosphamide, and allogeneic bone marrow (BM) transplantation. Long-term survivors were examined for residual BCL1 cells and for the ability to transfer adoptively graft vs. leukemia (GVL) activity. Residual BCL1 cells could not be detected in the allogeneic BM chimeras (greater than 14 to 16 months) with the use of indirect immunofluorescent staining with anti-idiotype antibody. However, residual tumor cells were present in 50% of the "cured" chimeric mice since adoptive transfer of 10(6) spleen cells from 50% of the treated chimeric mice caused leukemia in BALB/c recipients. In order to determine whether leukemia had been prevented in the "cured" chimeras by a persistent cell-mediated mechanism, BALB/c mice were injected with 10(6) spleen cells from the "cured" BM chimeras together with a dose of 10(2) or 5 x 10(5) BCL1 cells. Onset of leukemia was delayed or completely abolished in a significant proportion of recipients receiving the cell mixtures, suggesting the presence of anti-tumor immunity in the cured mice. The data suggest that a persistent active immune mechanism may be responsible, in part, for the significant antileukemic effects observed in mice tolerant to donor alloantigens.

Animals↗
PubMed1983

Total lymphoid irradiation.

Total lymphoid irradiation by itself can produce sufficient immunosuppression to prolong the survival of a variety of organ allografts in experimental animals. The degree of prolongation is dose-dependent and is limited by the toxicity that occurs with higher doses. Total lymphoid irradiation is more effective before transplantation than after, but when used after transplantation can be combined with pharmacologic immunosuppression to achieve a positive effect. In some animal models, total lymphoid irradiation induces an environment in which fully allogeneic bone marrow will engraft and induce permanent chimerism in the recipients who are then tolerant to organ allografts from the donor strain. If total lymphoid irradiation is ever to have clinical applicability on a large scale, it would seem that it would have to be under circumstances in which tolerance can be induced. However, in some animal models graft-versus-host disease occurs following bone marrow transplantation, and methods to obviate its occurrence probably will be needed if this approach is to be applied clinically. In recent years, patient and graft survival rates in renal allograft recipients treated with conventional immunosuppression have improved considerably, and thus the impetus to utilize total lymphoid irradiation for its immunosuppressive effect alone is less compelling. For example, in our institution, the current one-year patient and graft survival rates in recipients of kidneys from cadaver donors are 91 and 84 per cent in those treated with cyclosporine and 94 and 80 per cent in those treated with conventional immunosuppression. Similar results might also be achieved by protocols that use total lymphoid irradiation as an immunosuppressant, but it will be difficult to improve over the current results with cyclosporine or conventional immunosuppression, at least for primary transplantation. The future of total lymphoid irradiation probably lies in devising protocols in which maintenance immunosuppression can be eliminated, or nearly eliminated, altogether. Such protocols are effective in rodents. Whether they can be applied to clinical transplantation remains to be seen.

Adolescent↗
PubMed1983

Regulation of the immune response in experimental models of autoimmune disorders: I. Immunocompetence and transplantation tolerance in female (NZB X NZW)F1 hybrid mice immunosuppressed with total lymphoid irradiation and in reconstituted bone marrow chimeras.

Female (NZB X NZW)F1 (B/WF1) mice treated with fractionated total lymphoid irradiation (TLI) and TLI conditioned BALB/c leads to B/WF1 bone marrow (BM) chimeras were studied to determine the effects of TLI and reconstitution with normal BM on in vivo and in vitro immune reactivity. TLI treated B/WF1 females showed limited increased retention of semiallogeneic skin grafts (2 1/2 times as long as untreated) and allogeneic skin grafts (twice as long as untreated). In vitro proliferative responses to allogeneic lymphocytes were severely depressed at 5 days after TLI with partial recovery as early as 15 days post TLI. Proliferative responses to phytohemmagglutinin, concanavalin A and lipopolysaccharide were similarly depressed in the immediate post TLI period with gradual subsequent recovery. Nine out of eleven B/WF1 mice transplanted with semiallogeneic, BALB/c BM after TLI conditioning were stable chimeras without evidence of graft vs host disease and were permanently tolerant to BALB/c skin allografts in vivo and BALB/c alloantigens in vitro. BALB/c leads to B/WF1 chimeras showed BALB/c type in vitro proliferative mitogen responses without the age related decline in reactivity characteristic of untreated B/WF1. In contrast, adult B/WF1 mice were resistant to induction of completely allogeneic BM chimerism. The significance of these findings as they relate to the impaired immune status of female B/WF1 mice is discussed.

Animals↗
PubMed1983

Regulation of the immune response in experimental models of autoimmune disorders: resistance of (NZB X NZW)F1 mice to tolerance induction in vivo.

Studies were carried out to test whether tolerance to alloantigens and to heterologous proteins could be induced in (NZB X NZW)F1 (B/W) female mice, compared with females of various other mouse strains, including BALB/c, C3H/eb, C57Bl/Ka and (BALB/c X C57Bl/6)F1. Untreated BALB/c and B/W mice were resistant to tolerance induction by deaggregated BSA, while all other strains were susceptible, as indicated by their lack of response to antigen challenge. Tolerance induction to BSA was further potentiated in all mouse strains including BALB/c with the exception of B/W, following prior conditioning of the mice with total lymphoid irradiation (TLI). Similarly, specific and permanent tolerance to H-2 incompatible alloantigens was successfully induced in TLI conditioned BALB/c, C3H/eb, (BALB/c X C57Bl/6)F1 injected with bone marrow cells, however, B/W mice were resistant. Stable chimeras could be established in TLI treated B/W mice only across a semi-allogeneic combination (BALB/c--greater than B/W). No graft vs host disease (GVHD) was observed in any of the chimeras including B/W mice. We conclude that B/W mice are resistant to tolerance induction to heterologous proteins and alloantigens, even after TLI conditioning. We postulate that this phenomenon is a function of both the intrinsic properties of the haemopoietic stem cells, including their differentiated progeny, as well as characteristics of their cellular microenvironment.

Animals↗
PubMed1982

In vivo therapy of a murine B cell tumor (BCL1) using antibody-ricin A chain immunotoxins.

Prolonged remissions were induced in mice bearing advanced BCL1 tumors by the combined approach of nonspecific cytoreductive therapy and administration of a tumor-reactive immunotoxin. Thus, the vast majority of the tumor cells (approximately 95%) were first killed by nonspecific cytoreductive therapy using total lymphoid irradiation (TLI) and splenectomy. The residual tumor cells were then eliminated by intravenous administration of an anti-delta immunotoxin. In three of four experiments, all animals treated in the above fashion appeared tumor free 12-16 wk later. In one experiment, blood cells from the mice in remission were transferred to normal BALB/c recipients, and the latter animals have not developed detectable tumor for the 6 mo of observation. Because 1-10 adoptively transferred BCL1 cells will cause tumor in normal BALB/c mice by 12 wk, the inability to transfer tumor to recipients might indicate that the donor animals were tumor free. In the remainder of the animals treated with the tumor-reactive immunotoxin there was a substantial remission in all animals, but the disease eventually reappeared. In contrast, all mice treated with the control immunotoxin or antibody alone relapsed significantly earlier (3-4 wk after splenectomy).

Animals↗
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↗
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↗