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Biomedical subjects

R Storb

Publications and source records attributed to R Storb.

At least 487 records · Page 27Linked to original sources
PubMed1986

Fibronectin restores defective in vitro proliferation of patients' lymphocytes after marrow grafting.

In search for means of improving the impaired lymphocyte function of recipients after marrow grafting, we investigated the effect of fibronectin (FN) on patients' lymphocytes in allogeneic mixed lymphocyte cultures (MLC) and in cell-mediated lympholysis (CML) assays, since these tests are usually defective in transplanted patients. Four subgroups of marrow recipients were tested: patients within the first 100 days of transplantation (short-term) with (n = 16) or without (n = 14) acute graft-versus-host disease (GVHD), and long-term recipients with (n = 23) or without (n = 15) chronic GVHD. Exogenous FN (25 micrograms/ml) increased the proliferative response in the allogeneic mixed lymphocyte culture (MLC) significantly in cells from short-term patients without acute GVHD (+42%) and in those from long-term recipients with (+117%) and without chronic GVHD (+48%). In cells from patients with chronic GVHD, 3H-thymidine uptake after the addition of FN was enhanced to the level of that in lymphocytes of the corresponding marrow donor without exogenous FN. Fibronectin was effective only if added at the beginning of the MLC. In contrast to the results in MLC, exogenous FN failed to enhance phytohemagglutinin or OKT-3-induced lymphocyte proliferation and had no effect on CML activity. Moreover, FN did not show mitogenic activity in 3-6-day cultures. Our results demonstrate that FN in vitro is capable of restoring defective lymphocyte proliferation in marrow grafted patients, and circumstantial evidence suggests that this effect is mediated by an interaction between FN and monocytes.

Adolescent↗
PubMed1986

Marrow graft rejection and veno-occlusive disease of the liver in patients with aplastic anemia conditioned with cyclophosphamide and cyclosporine.

Based on studies in multiply transfused dogs showing that cyclosporine (CsA) pregrafting reduced the incidence of rejection, we treated 11 multiply transfused patients with severe aplastic anemia with CsA, 12.5-20 mg/kg/day i.m. on days -6 to -1, and cyclophosphamide, 50 mg/kg/day i.v. on days -5 to -2, followed on day 0 by a marrow graft from an HLA-identical sibling donor. Patients were not given additional infusions of buffy coat cells from their marrow donors. As postgrafting prophylaxis for graft-versus-host disease 10 patients were given CsA, 12.5 mg/kg/day orally, and one patient was given a standard regimen of intermittent methotrexate. Among 10 evaluable patients, 2 rejected their marrow grafts. Eight patients had sustained engraftment. Two of these developed severe veno-occlusive disease of the liver, a complication previously observed only in patients conditioned with total-body irradiation but not in more than 200 patients with aplastic anemia conditioned with cyclophosphamide without the addition of CsA. These data indicate that conditioning of patients with cyclophosphamide and concurrent CsA does not uniformly prevent graft rejection and can result in severe hepatic toxicity.

Adolescent↗
PubMed1986

Acute lymphoblastic leukaemia after bone marrow transplantation for aplastic anaemia.

An 11.5-year-old girl developed acute lymphoblastic leukaemia 7 months after bone marrow transplantation for severe aplastic anaemia. Before transplantation there were neither morphologic nor cytogenetic abnormalities to suggest preleukaemia. The conditioning regimen consisted only of cyclophosphamide. At the time of development of acute lymphoblastic leukaemia, chromosome analysis showed the blasts to be of host origin with clonal abnormalities including monosomy 7. Such a preleukaemic syndrome presenting as severe aplastic anaemia is a very rare event (the case reported here is the only one of 436 patients in Seattle) and cannot be reliably excluded before transplantation.

Acute Disease↗
PubMed1986

Canine platelet alloimmunization: the role of donor selection.

Five different platelet transfusion programmes were evaluated in a canine model to determine the most effective method of providing long-term platelet support. When a weekly transfusion from a single unrelated donor was used, alloimmune platelet refractoriness developed in 95% of recipients after an average of 3.1 +/- 0.7 transfusions, and donor platelets circulated for a total of 8.2 +/- 2.3 d. When multiple unrelated donors were used, the percentage of refractory recipients was similar (60% versus 77%) whether platelets came from six single donors given sequentially or from a pool of the same six donors given repeatedly. There was, however, a significant difference in the number of transfusions given prior to immunization (14 +/- 5 transfusions lasting 32 +/- 12 d for sequential single donors as compared to 5.5 +/- 1.0 transfusions lasting 13 +/- 2 d for the pooled donors). When littermates were used as platelet donors, the frequency of refractory recipients, the number of transfusions required to immunize, and the circulation time of donor platelets before refractoriness was not better than when multiple unrelated single donors were used. Furthermore, there was no significant difference in effectiveness between DLA-identical and DLA-nonidentical littermate platelet donors. In recipients previously immunized by a pool of six unrelated donors, the same percentage of recipients was refractory to DLA-identical littermate donors as had been observed following only DLA-identical platelet transfusions. This suggests that non-DLA immunizing platelet antigens, not shared between approximately 30% of DLA-identical littermates, are well represented in a random canine population. However, prior random transfusions did not compromise long-term platelet support from 'truly' platelet compatible DLA-identical littermate donors. These studies indicate that single donor transfusions either from littermates or sequential unrelated donors are the most effective method of providing long-term platelet support. However, the use of pooled unrelated donor transfusions, followed by DLA-identical donors in immunized recipients is an equally acceptable alternative.

Animals↗
PubMed1986

Marrow transplantation for severe aplastic anemia. Long-term outcome in fifty "untransfused" patients.

Fifty patients with severe aplastic anemia had no transfusions of blood products until just before marrow transplantation from HLA-identical family members. Of the 50, 42 are still alive 1 to 12 years after transplantation (median, 7 years). By actuarial standards, the 10-year probability of survival is 82%. Of the 42 surviving patients, 37 have Karnofsky performance status scores of 100% and 5 with chronic graft-versus-host disease have scores ranging from 50% to 90% (median, 80%). The 8 deaths were caused by early infection in 1, graft rejection in 1, acute graft-versus-host disease in 3, and chronic graft-versus-host disease in 3. All deaths occurred within two years after transplantation. The incidence of graft failure was 10%. Acute graft-versus-host disease developed in 14 of 44 patients at risk and chronic graft-versus-host disease, in 15 of 41. Risk factors for development of chronic graft-versus-host disease included increased age (p = 0.008) and presence of acute graft-versus-host disease (p = 0.001). The only factor associated with increased risk of death was development of acute graft-versus-host disease (p = 0.05). Results of this study extend our previous finding that patients with severe aplastic anemia who have transplants before the onset of transfusion-induced sensitization have an excellent probability of long-term survival and a normal life.

Acute Disease↗
PubMed1986

Inhibition of prostaglandin E2 restores defective lymphocyte proliferation and cell-mediated lympholysis in recipients after allogeneic marrow grafting.

Prostaglandins are said to influence T and B cell function by inhibiting the generation of interleukin 2 (IL 2) and the formation of suppressor lymphocytes. After bone marrow transplantation, patients usually have a profound immunodeficiency that persists in recipients with chronic graft-v-host disease (GVHD) and generally resolves in long-term survivors without GVHD. In vitro tests of lymphocyte function such as allogeneic mixed lymphocyte culture (MLC) and cell-mediated lympholysis (CML) have been shown to be impaired in many patients. We postulated that prostaglandin E2 (PGE2) plays a role in the impaired in vitro tests. To test this hypothesis, we studied in vitro tests in the presence of PGE2 antagonists, indomethacin, and anti-PGE2 antiserum with cells from 22 short-term patients (less than 100 days postgrafting) and 32 long-term survivors with or without GVHD. Results show that blockade of PGE2 release by indomethacin and anti-PGE2 significantly (P less than .01) enhanced the MLC (+67%) and the CML responses (+10.5%) of cells from long-term survivors with chronic GVHD but not from those of long-term, stable recipients. No enhancement of MLC and CML activity was observed with cells from donors of long-term recipients. In patients shortly after marrow grafting, enhancement in the MLC was not significant. However, CML activity in this patient group was significantly increased (+12.5% in recipients with no GVHD, 8.5% in those with acute GVHD, P less than .01). Indomethacin also suppressed the activity of nonspecific suppressor cells in patients with chronic GVHD. When cells from patients with chronic GVHD were treated with recombinant IL 2 and IL 2 combined with indomethacin, it was possible to get an additional augmentation of lymphocyte proliferation after the addition of indomethacin to IL 2-treated cultures. Thus it is very likely that PGE2 inhibits T lymphocyte proliferation, not exclusively by inhibition of IL2 production or activity. We conclude that PGE2, among other factors, may play a role in the pathogenesis of the immunodeficiency after transplantation. PGE2 does not act primarily by interfering with IL2 but presumably by inducing a suppressorlike activity.

Adolescent↗
PubMed1986

Second marrow infusion for poor graft function after allogeneic marrow transplantation.

Fifty-seven patients undergoing allogeneic marrow transplantation had persistent poor graft function after transplant and received a second marrow infusion from the original donor. Eight donors were HLA-non-identical family members and 49 were HLA-identical siblings. Poor function of the initial graft occurred in the absence of demonstrable rejection or persistent malignancy. Preparative reconditioning was not given before the second marrow infusion. Thirty-four of the 57 patients survived more than 1 month after the boost and were evaluated for haematopoietic recovery. All 34 subsequently achieved a neutrophil count of more than 500 X 10(6)/l and 20 became independent of platelet transfusions. Forty-nine (86%) of the 57 patients demonstrated acute graft-versus-host disease (GVHD). In 24 of the 49 patients GVHD increased in severity (10 patients) or first appeared (14 patients) after the boost. Chronic GVHD developed in all of the 20 patients who survived more than 150 days after the second infusion. Currently, 10 patients survive (median follow-up of more than 5 years) and all have normal haematologic function. Although haematologic reconstitution and increased GVHD occurred in some patients receiving second marrow infusions, the relation of these outcomes to the marrow boost is unclear in the absence of a control group.

Adolescent↗
PubMed1986

Is race a risk factor for allogeneic marrow transplantation?

We investigated the influence of race as a risk factor for the outcome of HLA-identical marrow transplantation. The actuarial survival at 2 years after grafting of Blacks, Hispanics and Asians was compared with that of Caucasians transplanted between 1971 and 1985 for aplastic anaemia, acute non-lymphocytic leukaemia and acute lymphoblastic leukaemia. Among patients with aplastic anaemia, there was no difference with regard to engraftment or actuarial survival among different racial groups. Among patients with acute non-lymphocytic leukaemia, Blacks had a lower survival (P = 0.03) than other groups, although there was no obvious single factor accounting for this difference. In patients with acute lymphocytic leukaemia, survival was comparable among the different races. Acute and chronic graft-versus-host disease appeared to occur with similar frequencies in all groups, except for a slightly higher incidence among Blacks with acute non-lymphocytic leukaemia. Larger numbers of patients need to be examined before firm conclusions can be drawn.

Actuarial Analysis↗
PubMed1986

Marrow transplantation for acute nonlymphoblastic leukemia in first remission: toxicity and long-term follow-up of patients conditioned with single dose or fractionated total body irradiation.

Seventy-five patients with acute nonlymphoblastic leukemia (ANL) in first remission were treated with cyclophosphamide, 60 mg/kg on each of two consecutive days followed by total body irradiation (TBI) at an exposure rate of 4-6 cGy/min from two opposing 60Co sources. The first 22 patients were given 9.2 Gy of TBI as a single dose. Subsequently 53 patients were randomized to receive either 10 Gy single dose TBI (n = 27) or 6 x 2 Gy fractionated TBI (n = 26). All patients received marrow transplants from HLA-identical siblings and all had sustained engraftment. Patients given 10 Gy of TBI had more early toxicity, especially veno-occlusive disease of the liver, than patients given 9.2 or 6 x 2 Gy of TBI. Idiopathic interstitial pneumonitis appeared to be more frequent in patients given 9.2 or 10 Gy single-dose TBI than in patients given 6 x 2 Gy fractionated TBI. Patients have now been followed from 5 to 9 years. Survival (+/- 95% confidence limits) at 5 years is 54 +/- 31% among patients given 9.2 Gy single dose TBI, 33 +/- 31% among patients given 10 Gy single dose TBI, and 54 +/- 26% among patients given 6 x 2 Gy fractionated TBI (P = 0.04). These results indicate that about half the patients with ANL transplanted while in first chemotherapy-induced remission can be expected to become long-term survivors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Prevention of graft-versus-host disease by immunosuppressive agents after transplantation of DLA-nonidentical canine marrow.

Dogs given 9.2 Gy of total body irradiation (TBI) followed by hematopoietic grafts from DLA-nonidentical unrelated or littermate donors and no postgrafting immunosuppression all develop acute graft-versus host disease (GVHD) and die within 3 weeks of grafting. Over a period of 10 years, the present study evaluated various immunosuppressive drugs either alone or in combination and compared their effectiveness to that of methotrexate (MTX) in preventing acute GVHD and prolonging survival. Among the single agents tested, 6-mercaptopurine and azathioprine resulted in a slight but significant prolongation of survival compared to controls, but they were less effective than MTX. Procarbazine and cytosine arabinoside were ineffective. Drugs tested in combination included MTX, cyclophosphamide, 6-mercaptopurine, azathioprine, cyclosporin, procarbazine, prednisone and antithymocyte globulin. Drug combinations, while effective in delaying the onset of GVHD, were associated with hematopoietic and other toxicities, which made their use impractical. Administration of MTX twice weekly proved to be no better than once weekly administration. Prednisone administered for the first 4 days after grafting in addition to MTX resulted in a modest improvement in survival. High-dose MTX (200 mg/kg) followed by leukovorin rescue resulted in severe early toxicity, both gastrointestinal and hematopoietic; however, some of those dogs which survived the early postgrafting period became stable long-term survivors. Most single agents tested in the present study proved to be either ineffective or were inferior to MTX in their ability to prevent GVHD. None of the drug combinations tested was as effective as the one involving MTX/cyclosporin reported previously.

Acute Disease↗
PubMed1986

Acute and chronic graft-versus-host disease: clinical manifestations, prophylaxis, and treatment.

Graft-versus-host disease (GvHD) is a clinical syndrome observed in recipients of allogeneic marrow grafts, presumably due to an attack of donor T-lymphocytes against host (patient) tissue. Acute GvHD develops within the first 2-3 months of transplantation and occurs in 25-60% of recipients of HLA genotypically identical transplants. The major target organs are skin, liver, intestinal tract, and conjunctivae. About one-half of the patients with moderately severe to severe GvHD die, generally from associated infections. Attempts at prevention of acute GvHD, such as selection of HLA-identical donors, postgrafting immunosuppression, decontamination of the patient and placement in a sterile environment, or T-cell depletion of the donor marrow, have met with only partial success. Treatment of established GvHD involves the use of immunosuppressants, such as steroids, antithymocyte globulin, cyclosporine, and monoclonal antibodies. Chronic GvHD generally develops 3 months to 1 year after grafting and affects 40-45% of surviving patients. Target organs, in addition to those of acute GvHD, include exocrine glands and mucous and serous membranes. The clinical picture strongly resembles collagen vascular diseases. Chronic GvHD occurs more frequently in older patients and patients with preceding acute GvHD. These patients are susceptible to bacterial or fungal infections that may be fatal. Treatment of chronic GvHD involves the use of immunosuppressive and cytotoxic drugs and prophylactic antibodies.

Acute Disease↗
PubMed1986

Ultraviolet irradiation of blood prevents transfusion-induced sensitization and marrow graft rejection in dogs.

In a canine model using DLA-identical littermate pairs, we have shown that a regimen of three transfusions of donor blood given 24, 17, and 10 days before transplant uniformly leads to marrow graft rejection, presumably due to sensitization to minor (non-DLA) histocompatibility antigens. Untransfused dogs uniformly achieve sustained engraftment. In the present study, we investigated whether the exposure of blood to ultraviolet (UV) light (220-300 nm) prior to transfusion prevented sensitization of the recipient and allowed for successful marrow engraftment. Ten dogs were each given three pretransplant transfusions from the marrow donor. Each transfusion consisted of 50 mL of whole blood exposed in vitro to UV light for a total of 1.35 J/cm2. All ten dogs achieved engraftment. In contrast, all four dogs that had received sham-exposed transfusions rejected their grafts. In vitro studies revealed that although cell viability was not affected, leukocytes contained in UV-exposed blood were unable to function as stimulator cells in mixed leukocyte cultures or as accessory cells in mitogen-stimulated cultures. These data are consistent with the hypothesis that accessory cells are involved in transfusion-induced sensitization. We conclude that in vitro exposure of blood to UV light before transfusion prevents sensitization and allows for subsequent marrow engraftment.

Animals↗
PubMed1986

Erythropoietic reserve in marrow-transplanted dogs.

The effect of marrow transplantation on erythropoiesis was studied in three normal dogs (T0), three irradiated dogs receiving compatible marrow (T1), and three irradiated dogs (T2) who donated their marrow to a recipient animal and then at a later date underwent a marrow transplant from the initial marrow recipient. Plasma iron turnover was measured (a) under basal conditions, (b) after plasma iron was elevated by iron infusion, and (c) after hemolytic anemia had been produced by phenylhydrazine. Basal plasma iron turnover in T0, T1, and T2 animals averaged 1.3, 1.0, and 1.3 mg/dl whole blood/day. Turnover of the three groups increased to 7.1, 6.2, and 6.4 mg/dl whole blood/day after the induction of anemia by phenylhydrazine. These values were converted from the transferrin saturation present at the time of the measurement to the calculated turnover at 100% saturation, thereby expressing the maximum capacity of tissues to assimilate iron. After this correction, the calculated maximum uptake was shown to be increased over basal by 3.7, 4.0, and 3.8 times. To validate this approach, an additional comparison was made between baseline turnovers at elevated levels of plasma iron and anemic animals at similarly elevated plasma iron levels. The increment of the three groups was shown to be 3.7, 3.9, and 4.0 times basal. These studies illustrate the use of a refined method of ferrokinetic evaluation of erythropoiesis and indicate that the proliferative reserve in transplanted animals is unimpaired.

Anemia↗
PubMed1986

Bone marrow transplantation experience for children with aplastic anemia.

From May 1971 through December 1981, 81 children (22 months to 17 years of age) received allogeneic bone marrow grafts for severe aplastic anemia. All donors were HLA-identical family members. Fifty-seven of the 81 (70%) are still alive. Twenty-three untransfused patients were conditioned with cyclophosphamide, 50 mg/kg/d, for four days, and 19 (83%) have survived from 5 to 12 years. All 58 transfused patients were conditioned with cyclophosphamide, 50 mg/kg/d, for four days, 11 received additional immunosuppression, and 19 received posttransplantation donor buffy coat cells. Thirty-eight (65%) have survived from 3 to 13 years (P = .1). In a multivariate analysis, the only factor significantly associated with increased survival among patients with sustained grafts was the absence of significant graft v host disease (P less than .0001). The factors significantly related to increased rejection were low bone marrow cell dose (P less than .05) and positive relative response in mixed leukocyte culture (P less than .0001), but the addition of buffy coat cells did not significantly influence graft rejection. The development of grades II to IV acute graft v host disease was associated with random donor platelet refractoriness (P less than .05) and donor/recipient sex differences (P less than .05). Patients at highest risk for chronic graft v host disease were those patients who developed significant acute graft v host disease (P less than .01) and who received buffy coat infusions (P less than .025). All patients who were untransfused had a negative relative response and were not refractory to random donor platelets.

Acute Disease↗
PubMed1986

The detection of specific antibody formation to recall antigens after human bone marrow transplantation.

The results of this study show that donor-derived immunity can be detected and persists in long-term survivors with and without chronic graft-v-host disease (GVHD) after human marrow grafting. Seventy-one marrow recipients (60 long-term and 11 short-term survivors) were studied for the presence of specific serum IgG antibodies to tetanus toxoid (TT), and 46 marrow recipients (35 long-term and 11 short-term) were tested for antibodies to diphtheria toxoid (DT) and measles virus after marrow grafting using an enzyme-linked immunosorbent assay. Of the 60 long-term survivors, 31 were healthy and 29 had chronic GVHD. None of the recipients were immunized to the test antigens postgrafting. Most long-term healthy recipients exhibited antibody titers to the recall test antigens, whereas only a minority of those with chronic GVHD had antibody titers to recall antigens. In healthy long-term recipients (greater than or equal to one year postgrafting) whose donors were immune to the test antigens, 25 of 31 had titers to TT, 11 of 17 had titers to DT, and 12 of 20 had titers to measles. In recipients with C-GVHD, 13 of 29 had titers to TT, six of 15 had titers to DT, and six of 15 had titers to measles virus. Within 100 days postgrafting, 11 of 11 had anti-TT titers, ten of ten had anti-DT titers, and seven of eight had antimeasles virus titers.

Antibodies↗
PubMed1986

Bone marrow transplantation in patients aged 45 years and older.

Increasing age has been reported to be a poor prognostic factor for survival after bone marrow transplantation. We evaluated causes of death and frequency and type of complications after marrow grafting in 24 syngeneic and 39 allogeneic recipients who were 45 to 68 years old at the time of transplant. Most patients were in an advanced stage of hematologic malignancy. Among patients given syngeneic transplants, actuarial disease-free survival at 7 years is 20%. The major causes of death were relapse of leukemia and idiopathic interstitial pneumonia. Among allogeneic recipients, 9 (23%) are currently alive, and actuarial disease-free survival at 7 years is 11%. Cytomegalovirus pneumonia and septicemia were the most frequent causes of death. Patients over 50 years of age had the poorest survival rate (1/13), but many of these were transplanted in an advanced stage of their disease. However, among 12 patients transplanted while in remission or at an early stage of their disease, 5 are surviving 65 to 1,160 days after transplantation, with an actuarial survival rate of 22% at 3 years. This is in contrast to those who received their transplant in relapse: 2 out of 20 patients (10%) became long-term survivors, with a probability of survival of 15% at 3 years. The actuarial incidence of grade II through IV acute graft-v-host disease (GVHD) was 30% for allogeneic recipients 45 to 50 years of age. This was not significantly different from the incidence in younger patients. In patients 51 to 62 years of age, the actuarial incidence of acute GVHD was 79%; however, this group included three partially HLA-mismatched transplants. Ten of 15 patients surviving at least 3 months developed chronic GVHD. These results suggest that marrow transplantation is feasible and should be considered in patients over 45 years, especially if recipients are in good clinical condition and are at an early stage of their disease, such as the chronic phase of chronic myelogenous leukemia and preleukemia. For patients more than 50 years of age, allogeneic marrow grafting cannot presently be considered first-line therapy.

Adult↗
PubMed1986

Mixed hematologic chimerism after allogeneic marrow transplantation for severe aplastic anemia is associated with a higher risk of graft rejection and a lessened incidence of acute graft-versus-host disease.

Ninety-six patients with severe aplastic anemia who received a sex-mismatched, HLA-identical allogeneic sibling marrow transplant had sequential cytogenetic analyses performed to determine the incidence and implications of posttransplant mixed hematologic chimerism. Of the 96 patients, 56 (58.3%) became mixed chimeras with coexisting host and donor cells detected in peripheral blood or marrow 14 days or later after transplant, and 40 patients (41.7%) were complete chimeras with 100% donor-type hematopoietic cells. The incidence of mixed chimerism was independent of prior blood production transfusions and infusion of donor buffy coat. The rejection rate was significantly increased in the mixed chimeric group, particularly in patients not receiving buffy coat (14 of 36 rejecting), although overall, the majority (69.7%) retained their first graft. Rejection was seen almost exclusively in patients exposed to multiple transfusions before transplantation. If patients who reject their first graft are censored, the overall incidence of grades II through IV acute graft-v-host disease (GVHD) was significantly reduced in those with mixed chimerism. Transfused patients with mixed chimerism in particular were less likely to develop grades II through IV acute GVHD. The incidence of chronic GVHD was similar in the two groups and did not significantly influence survival. In this study, mixed chimerism persisted for up to 395 days posttransplant, either the first graft being rejected or, more commonly, hematopoiesis reverting to 100% donor-type cells. Mixed lymphohematopoietic chimerism may persist in patients with aplastic anemia who have received matched allogeneic marrow transplants for significant periods before hematopoiesis reverts to donor cell type.

Adolescent↗