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Biomedical subjects

R Storb

Publications and source records attributed to R Storb.

At least 433 records · Page 24Linked to original sources
PubMed1988

Cyclosporine v methotrexate for graft-v-host disease prevention in patients given marrow grafts for leukemia: long-term follow-up of three controlled trials.

One hundred seventy-nine patients with acute nonlymphoblastic leukemia in first remission (n = 75), chronic myelocytic leukemia in chronic or accelerated phase (n = 48) or leukemia in advanced stage (n = 56) were given HLA-identical marrow grafts and randomized to receive methotrexate or cyclosporine for prevention of graft-v-host disease (GVHD). The current report updates the three prospective trials with follow-ups ranging from 3.2 to 6.2 years after marrow grafting. Results were analyzed separately for each individual study and for all three studies combined. Overall, 40% of patients given cyclosporine and 55% of those given methotrexate developed acute GVHD (P = .13); the incidence of chronic GVHD was 42% and 48%, respectively (P = .67). Twenty-two percent of cyclosporine-treated patients and 30% of methotrexate-treated patients developed interstitial pneumonia of any etiology (P = .25), and the figures for cytomegalovirus pneumonia were 18% and 20%, respectively (P = .41). The overall incidence of leukemic relapse was 31% in cyclosporine-treated patients and 36% in methotrexate-treated patients (P = .75). The probabilities of survival for cyclosporine-v methotrexate-treated patients were comparable for all three study groups: 52% v 48% in patients with acute nonlymphoblastic leukemia (P = .42), 55% v 60% for those with chronic myelocytic leukemia (P = .61), 12% and 12% for those with advanced leukemia (P = .93), and 39% v 38% overall (P = .72). We conclude that cyclosporine and methotrexate are comparable regarding the likelihood of acute/chronic GVHD, interstitial pneumonia, leukemic relapse, and long-term survival.

Acute Disease↗
PubMed1988

Canine model for gene therapy: inefficient gene expression in dogs reconstituted with autologous marrow infected with retroviral vectors.

Successful retroviral gene transfer into murine hematopoietic stem cells indicates the potential for somatic gene therapy in the treatment of certain human hereditary diseases. We developed a canine model to test the applicability of these techniques to a preclinical model of human marrow transplantation. Previously we reported that canine CFU-GM could be infected with retroviral vectors carrying either the gene for a mutant dihydrofolate reductase (DHFR) or neomycin phosphotransferase (NEO). This study reports six lethally irradiated dogs transplanted with autologous marrow cocultivated with retroviral vector-producing cells. This procedure conferred drug resistance to 3% to 13% of the CFU-GM. Three dogs infected with either the NEO or DHFR virus engrafted, but we detected no drug-resistant CFU-GM. Three dogs were given marrow infected with a DHFR virus and received methotrexate (MTX) as in vivo selection; all three had evidence of engraftment. In the surviving dog, we detected 0.03% to 0.1% MTX-resistant CFU-GM at 3 to 5 weeks posttransplant during in vivo selection. These results indicate that we can reconstitute lethally irradiated dogs with autologous marrow exposed to retroviral vectors and suggest that gene transfer into hematopoietic cells is feasible on a large scale. However, the low-level transient gene expression indicates that considerable obstacles remain before human gene therapy can be considered.

Animals↗
PubMed1988

Functional dendritic cells are required for transfusion-induced sensitization in canine marrow graft recipients.

Untransfused dogs given 9.2 Gy total-body irradiation and hematopoietic grafts from DLA-identical littermate donors uniformly achieve sustained engraftment, whereas dogs given three transfusions (Tx) of whole blood from the intended marrow donor 24, 17 and 10 days pretransplant uniformly reject their graft. Sensitization appears to be mediated by peripheral blood mononuclear cells and can be prevented by prior irradiation of the Tx product with UV light, known to inactivate leukocytes, in particular, cells with accessory function. In the present study we investigated which leukocyte population was responsible for Tx-induced sensitization and subsequent marrow graft rejection. Surprisingly, neither monocytes nor macrophages or dendritic cells induced sensitization, and all dogs so treated achieved engraftment; however, all four evaluable dogs transfused with UV-exposed blood to which small numbers of normal dendritic cells (12.5 x 10(3)/kg) were added rejected their marrow graft. Among five dogs given UV-exposed blood and normal monocytes (12.5 x 10(3)/kg) only one rejected its graft, and four achieved sustained engraftment. We conclude that donor dendritic cells are necessary, albeit not sufficient for in vivo sensitization. Sensitization is prevented by elimination or inactivation of dendritic cell.

Animals↗
PubMed1988

Allogeneic marrow transplantation for children with juvenile chronic myelogenous leukemia.

Fourteen children between the ages of 2 and 5 years with juvenile chronic myelogenous leukemia were given cyclophosphamide, total-body irradiation, and marrow transplants. Unmodified marrow was given to six patients who received marrow from HLA-identical siblings and eight patients who received marrow from family members HLA identical for one haplotype but mismatched for one to three loci on the nonshared haplotype. Five patients died of transplant-related complications, and three relapsed at 48, 81, and 1,670 days posttransplant and died of leukemia. Six patients survive in continuous remission from 0.5 to 11.5 years posttransplant.

Bone Marrow Transplantation↗
PubMed1988

Phenotypic characterization of canine lymphoma, using monoclonal antibodies and a microlymphocytotoxicity assay.

Cells acquired from lymph node biopsy specimens obtained from 58 dogs scheduled to undergo chemotherapy for lymphoma were immunophenotyped, using a microlymphocytotoxicity (MLCT) assay comprising a panel of well-characterized monoclonal antibodies (MAB) specific for canine cell surface antigens. Cells from 54 of the dogs concurrently were tested cytofluorometrically, using surface immunoglobulin (SIg) as a marker for B cells and the MAB DT2 specific for peripheral blood T cells. The MLCT results indicated frequent coexpression of antigens identified by DT2 antibody and, to a lesser extent, by 1A1 antibody on SIg-positive cells, suggesting that these antigens may be associated with other types of less-differentiated lymphoid cells, in addition to being associated with mature T cells. Class-II major histocompatibility antigens, as recognized by MAB H81.98.71, HB10a, and H40.315.7, were detected on most SIg-positive cells, but generally were lacking on SIg-negative, DT2-negative cells. The MAB Wig4, reactive with canine monocytes, recognized relatively few cells (11 of 58). Response to chemotherapy was not correlated with reactivity to MAB DLy6 specific for resting lymphocytes or to MAB W3G10 specific for a polymorphic antigen associated with the canine major histocompatibility complex. The MLCT assay appears to be efficient, rapid, and inexpensive for immunophenotyping cells from lymphoma biopsy specimens.

Animals↗
PubMed1987

In vitro immunoglobulin production, proliferation, and cell markers before and after antithymocyte globulin therapy in patients with aplastic anemia.

Peripheral blood lymphocytes from 16 aplastic anemia patients were studied for in vitro biosynthesis of immunoglobulins (Ig), proliferative responses, and cell markers before and after antithymocyte globulin (ATG) treatment in an attempt to identify immune functions that would be useful in predicting responses to ATG therapy. Six of the 16 aplastic anemia patients were complete responders to ATG therapy, two were partial responders, and eight failed to respond to ATG therapy. The proportion of E+, CD4, CD8, and surface Ig-positive cells did not correlate with in vitro lymphocyte functions nor clinical responses before or after ATG therapy. Lymphocyte proliferative responses to phytohemagglutinin, tetanus toxoid, alloantigens, or pokeweed mitogen were generally present before and after ATG therapy. When pokeweed mitogen, herpes simplex type I virus, and tetanus toxoid were used as probes to elicit in vitro Ig production using a hemolytic plaque assay, some patients had 1) B cells that failed to produce Ig, 2) T cells that failed to provide helper activity, and 3) T cells that exhibited excessive suppressor activity in the various antibody production systems. These measures of immune function, however, did not correlate with clinical responses to ATG therapy.

Anemia, Aplastic↗
PubMed1987

Engraftment of DLA-nonidentical bone marrow facilitated by recipient treatment with anti-class II monoclonal antibody and methotrexate.

Marrow transplants were carried out between unrelated DLA-nonidentical dogs. Recipients were prepared for transplantation by 9.2 Gy single-dose total-body irradiation (TBI) administered at 7 cGy/min. All recipient dogs received marrow, 4 X 10(8) cells/kg, and no buffy coat cells. In addition to TBI, 19 dogs were given anti-class II monoclonal antibody (mAb) 7.2, either alone or combined with a second anti-class II mAb, HB10a, at doses of 0.2 or 0.4 mg/kg/day on days -5 to 0 or -1 to +3. Seven had hemopoietic engraftment. Ten dogs were given, in addition to TBI, methotrexate (MTX), 0.4 mg/kg/day on days 1, 3, 6, and 11 after grafting, and six had engraftment. Ten dogs were given a combination of mAb 7.2 pregrafting and MTX after grafting, and 9 had evidence of engraftment. Among 7 dogs treated with the irrelevant mAb 31E6.4, only one had engraftment. Thus the administration of anti-class II mAb pregrafting and MTX postgrafting had a beneficial effect in overcoming resistance to histoincompatible marrow grafts. Possibly this effect is more pronounced when both approaches are combined.

Animals↗
PubMed1987

Phenotypical and functional studies on a subtype of suppressor cells (CD8+/CD11+) in patients after bone marrow transplantation.

Dual labeling with the monoclonal antibodies anti-Leu 2 (fluorescein-conjugated) and anti-Leu 15 (phycoerythrin-conjugated) was used to phenotype and sort the lymphocytes from 12 short-term (100 days postgrafting) recipients, 8 long-term (6 months postgrafting) stable, and 11 long-term patients with chronic graft-versus-host disease (GVHD). The proportion of Leu 2+ 15+ cells was increased in 11 of 12 short-term patients (mean + SEM: 31% +/- 3.6)-and in 6 of 11 patients with chronic GVHD (18% +/- 2.4) compared with normal controls (n = 8; 7.5% +/- 1.9). However, there was no correlation between proportions of Leu 2+ 15+ or Leu 2+ 15- cells and the presence of acute GVHD. Long-term patients with chronic GVHD tended to have a higher proportion of Leu 2+ 15- cells. To functionally characterize these two T cell subsets, Leu 2+ 15- and Leu 2+ 15+ subsets were sorted from purified T cells obtained from two recipients and one normal subject. Both Leu 2+ 15+ and Leu 2+ 15- cells from a short-term patient suppressed pokeweed mitogen--stimulated immunoglobulin production of normal B cells. Leu 2+ 15- cells from a long-term survivor with chronic GVHD and the normal control provided help, whereas the Leu 2+ 15+ cells also strongly suppressed immunoglobulin synthesis. The suppressor activity of the Leu 2+ 15+ subset in all three individuals was radiosensitive (12 Gy). These results illustrate the need for careful correlative phenotyping and functional studies. Furthermore, these studies clearly demonstrate that different functions may exist within a particular T cell phenotype after bone marrow transplantation.

Adolescent↗
PubMed1987

Facilitation of engraftment of DLA-nonidentical marrow by treatment of recipients with monoclonal antibody directed against marrow cells surviving radiation.

Past studies in dogs have suggested that marrow graft rejection was mediated by major histocompatibility complex (MHC) class II antigen-positive non-T cells that survived standard doses of total-body irradiation (TBI). We have now raised 4 monoclonal antibodies (mAbs) against marrow cells harvested 6 days after TBI. The mAbs are highly reactive (greater than 70%) with marrow cells surviving radiation and also bind strongly (greater than 50%) to normal marrow cells, lymphocytes, monocytes, and granulocytes. One of the mAbs (34-S3) reacted strongly with NK-like cells. In vitro treatment of marrow with mAb and rabbit complement (C') did not affect erythroid colony-forming unit (CFU-E) growth, whereas 2 of the 4 mAbs inhibited granulocyte-macrophage colony-forming unit (CFU-GM) growth, and all 3 mAbs tested suppressed autologous marrow engraftment. One of the mAbs, 69-S5 (IgG1), bound to a 95,000 dalton antigen. It crossreacted with human cells, but not with cells from Rhesus monkeys, baboons, and cats. We administered this mAb intravenously at 0.2 mg/kg/day on days -5 to 0 to dogs given 9.2 Gy TBI on day 0 followed by marrow grafts (less than or equal to 4 x 10(8) cells/kg) from DLA-nonidentical unrelated donors. Three of five dogs had sustained grafts. Increasing the dose of mAb ten-fold (2 mg/kg/day) resulted in graft failure (2 of 2 dogs). Treatment with a dose of 0.2 mg/kg/day from day -7 to -2 showed sustained engraftment in 7 of 10 dogs. This result is in contrast to sustained grafts in 3 of 36 dogs not given mAb, and in 1 of 7 dogs treated with an irrelevant mAb (P = 0.0002 and 0.04, respectively). We conclude that treatment of recipients with a mAb raised against marrow cells surviving radiation and not directed at major histocompatibility complex (MHC) class II antigens and NK-like cells can also facilitate engraftment of DLA-nonidentical canine marrow. These results may be relevant for the transplantation of HLA-incompatible marrow in man, particularly after in vivo T cell depletion, where graft failure is frequent.

Animals↗
PubMed1987

Specific tolerance and immunocompetence in haploidentical, but not in completely allogeneic, canine chimeras treated with methotrexate and cyclosporine.

Recipient dogs were conditioned with 9.2 Gy of total-body irradiation followed by the infusion of bone marrow and peripheral blood leukocytes from a DLA-haploidentical littermate (N = 10) or a completely allogeneic unrelated donor (n = 9). Graft-vs.-host disease (GVHD) prophylaxis consisted of methotrexate (MTX) and cyclosporine (CsA). Postgrafting all dogs were complete lymphohemopoietic chimeras. Lymphocytes of haploidentical chimeras without GVHD were unresponsive to stimulation by host lymphocytes cryopreserved pregrafting. Lymphocytes of haploidentical chimeras with GVHD proliferated in response to host cells, albeit less than donor cells pregrafting. In completely allogeneic chimeras, neither lymphocytes from dogs with GVHD, nor those from dogs without the disease showed responses to host lymphocytes. In addition, cells from haploidentical chimeras obtained early after transplantation nonspecifically suppressed donor cell proliferation. Later on, lymphocytes from dogs without GVHD showed specific suppression of donor cells, while lymphocytes from chimeras with GVHD continued to show nonspecific suppression. Cells from completely allogeneic chimeras both with and without GVHD never suppressed donor cells specifically. Both specific and nonspecific suppressor cells were enriched by nylon wool adherence, expressed T cell markers, and were not affected by the addition of indomethacin. Even after removing nylon wool-adherent cells, however, chimera cells were unresponsive to stimulation by host cells. By one year after transplant, chimera lymphocytes no longer showed suppression. In cell-mediated lympholysis assays, lymphocytes from all chimeras, regardless of GVHD, failed to generate cytotoxic cells against host cell targets. However, while haploidentical chimeras showed cytotoxicity against third-party targets, completely allogeneic chimeras did not. This deficiency was not overcome by the addition of mixed leukocyte culture supernatant or donor lymphocytes. All chimeras had basically normal antibody responses to keyhole limpet hemocyanin and phage X174. However, while haploidentical chimeras had normal responses to bacillus Calnette-Guerin (BCG) sensitization and rejected DLA-incompatible skin grafts within the normal time frame, completely allogeneic chimeras were not sensitized by BCG and showed delayed skin graft rejection. Histopathological studies revealed slow thymic reconstitution in all chimeras, particularly in the presence of GVHD. However, while healthy haploidentical chimeras eventually showed thymic histology normal for age, completely allogeneic chimeras did not.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

A DLA-associated polymorphic cell surface determinant defined by the murine monoclonal antibody W3G10.

A polymorphic determinant on the surface of canine peripheral blood mononuclear cells (PBMC) has been identified using the murine monoclonal antibody W3G10. The determinant, which has a molecular weight of approximately 39 Kd, is associated with DLA-Dw1 (w = workshop designation), -Dw3, -Dw4, -Dw10, -Dsea1 (sea = Seattle designation) and -Dsea9, but not -Dw8, -Dw9, -Dsea4, -Dsea10, -Dsea16 or -Dsea17, and segregates in Mendelian fashion. There does not appear to be any linkage disequilibrium with currently recognized DLA-A, -B or -C alleles. Cytotoxic effector function was eliminated when W3G10 positive alloantigen primed PBMC were treated with W3G10. However, cytotoxicity was not affected when W3G10 negative PBMC were used, thus further confirming polymorphism. The data suggest that the antigen identified by McAb W3G10 is not a typical class I or class II MHC antigen, but may be encoded by a closely linked gene.

Alleles↗
PubMed1987

Does histologic grading of inflammation in bone marrow predict the response of aplastic anaemia patients to antithymocyte globulin therapy?

We tested the hypothesis of teVelde and Haak that the degree of bone marrow inflammation in aplastic anaemia might correlate with an immunological process responsive to immunosuppressive therapy. 120 patients with aplastic anaemia but no suitable marrow donor were treated with horse antithymocyte globulin (ATG) and 53 who had matched sibling donors with bone marrow transplants. Pretreatment bone marrow histology in methacrylate and paraffin specimens was graded by degree of inflammatory infiltrate in a four-tiered system. High grade (II-III) was compared to low (O-I) as a correlate of response to ATG. Complete and partial response to ATG was seen in 50% of patients with high grade marrow and 31% of patients with low grade marrow (P = 0.099). Only one of four patients with grade III inflammation responded significantly to ATG treatment. Median survival following ATG therapy was similar in both groups as well. There was a significantly lower median age in the patients with low grade (24.5 years) versus high grade (37.5 years) inflammation (P = 0.016). Grade also had no prognostic value in the marrow transplant group.

Adolescent↗
PubMed1987

Marrow transplantation: what determines success or failure of hematologic reconstitution?

The technique of marrow transplantation serves to replace diseased marrow by normal hemopoiesis. Successful restoration of hemopoiesis is predicated upon the ability of the preparative regimen to ablate both the diseased marrow and the host immune system and upon the capacity of the injected undifferentiated self-renewing stem cells to produce progeny. If these conditions are met, hemopoiesis and an immune system consisting almost exclusively of donor cells will be established although a minority of patients may show a mixture of host and donor cells. If not, graft failure may ensue, a clinical syndrome having at least two etiologies: spontaneous graft resistance and transfusion-induced sensitization. The present report contrasts the immunological findings made with successful hemopoietic engraftment to those seen with graft failure.

Animals↗