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Biomedical subjects

R P Witherspoon

Publications and source records attributed to R P Witherspoon.

At least 73 records · Page 4Linked to original sources
PubMed1988

Transfer of specific immunity in marrow recipients given HLA-mismatched, T cell-depleted, or HLA-identical marrow grafts.

The transfer of tetanus toxoid (TT) and diphtheria toxoid (DT) specific immunity was evaluated in 209 short-term (less than 120 days postgrafting) and 257 long-term (greater than 198 days postgrafting) non-boosted recipients after HLA-identical, HLA non-identical, and HLA-identical T cell-depleted marrow transplantation. TT or DT immunizations were not given to donors in the 6 months prior to transplant and the recipients received no immunizations post-transplantation. In 209 short-term recipients, 94% and 74% of recipients had detectable anti-TT and anti-DT titers respectively. In long-term recipients, 110 of 210 (52%) who received HLA-identical grafts, 17 of 38 (45%) who received HLA-non-identical grafts, and seven of seven (100%) who received HLA-identical T cell-depleted grafts had anti-TT titers; and 86 of 212 (40%) who received HLA-identical grafts, 11 of 38 (29%) who received HLA-non-identical grafts, and four of seven (57%) who received HLA-identical T cell-depleted grafts had anti-DT titers. When compared to non-boosted normal donor and control subjects, the magnitudes of anti-TT and anti-DT titers from the recipients were comparable to controls. These data show that transferred specific immunity is detectable in long-term recipients of T cell-depleted or HLA-non-identical grafts without immunizations of donors or recipients before or after transplantation.

Antibodies↗
PubMed1988

Use of thymic grafts or thymic factors to augment immunologic recovery after bone marrow transplantation: brief report with 2 to 12 years' follow-up.

Thymus tissue implants, thymic epithelial cells obtained from third party donors sharing one HLA-A and -B locus with the recipient, or the thymic hormones thymosin fraction 5 and thymopentin were given to recipients of HLA-identical sibling bone marrow to prevent chronic graft-versus-host disease (GVHD) and accelerate immunologic reconstitution. The clinical courses of 17 patients receiving thymus tissue and 18 patients receiving thymic hormones were reported initially 5 years ago and showed no difference in the incidence of chronic GVHD or immunologic recovery from those of concurrent or historical controls. We report here for the first time nine new patients who received thymus tissue implants with modifications of the culture method to lower the number of lymphocytes in the transplanted tissue with the intent of reducing rejection of the thymus tissue grafts. The clinical outcomes and immunologic functions of these nine patients were similar to those of the recipients of the earlier thymus tissue implants. With follow-up now ranging from 2.2 to 12.3 years (median 6.7) for the total group, 16 patients are alive. Seven never developed chronic GVHD. Nine were treated for chronic GVHD, seven of whom recovered and are leading normal lives, one has chronic pulmonary insufficiency, and one is disabled from chronic GVHD. We conclude that thymus tissue grafts or thymic epithelial cells partially HLA-matched to the recipient, thymosin fraction 5, or thymopentin used as described were not effective in reducing the incidence of chronic GVHD, improving immunologic recovery, or altering long-term survival.

Adolescent↗
PubMed1988

Graft failure in patients receiving T cell-depleted HLA-identical allogeneic marrow transplants.

Results of a previous study suggested that the risk of graft failure after transplantation of HLA-identical T cell-depleted marrow may be influenced by the preparative regimen. Subsequent clinical trials were carried out to clarify this relationship and to determine whether post-transplant immunosuppression could have an effect on graft durability. Two factors were found to be associated with graft failure. Patients with hematologic malignancy given a preparative regimen of cyclophosphamide (120 mg/kg) and 15.75 Gy fractionated total body irradiation (TBI) had a 27% cumulative incidence of graft failure, which was less than the 69% incidence seen previously in patients given cyclophosphamide and 12.0 Gy fractionated TBI (p less than 0.05, log-rank test). Patients with acute leukemia had a higher risk of graft failure than patients with chronic myelogenous leukemia (p less than 0.005). The incidence of graft failure was not influenced by post-transplant immunosuppression with cyclosporine, methotrexate or a combination of cyclosporine plus methotrexate or by the omission of all post-transplant immunosuppression. Similarly, graft failure was not associated with the complement lot used for marrow treatment, the recovery of BFU-E or CFU-GM, or with the number of nucleated cells or T cells in the graft. The effect of primary diagnosis and the inverse relationship between the amount of pretransplant TBI and the graft failure rate suggest that a host factor may have been involved in a presumably immune-mediated rejection. This observation further leads to the inference that certain T cells present in donor marrow can suppress host immunity or help to maintain function of the graft.

Adult↗
PubMed1988

HLA-identical marrow transplantation during accelerated-phase chronic myelogenous leukemia: analysis of survival and remission duration.

Results of HLA-identical allogeneic marrow transplantation were analyzed for 66 patients with accelerated-phase chronic myelogenous leukemia (CML). Multivariate proportional hazards regression models were used to determine disease-related and transplant-related factors associated with posttransplant mortality and relapse. The projected 5-year survival rate was estimated at 18% by the product-limit method. The major causes of death were interstitial pneumonia, infection, and relapse. Splenomegaly at initial diagnosis and longer time interval from diagnosis to transplant were associated with decreased overall survival and event-free survival. Sixteen patients have relapsed between 17 and 1,569 days (median, 486) posttransplant. The use of T-cell-depleted marrow and older age of the donor or recipient were associated with an increased probability of leukemic relapse. Ten of the 16 relapses occurred among the 15 patients who received T-cell-depleted marrow. The actuarial relapse risk 2.5 years posttransplant was 100% in patients administered T-cell-depleted marrow as compared with 25% in patients administered unmodified marrow. The data in this report emphasize the increased risks and relatively poor results that occur when marrow transplantation is deferred until after signs of acceleration appear. When compared with results for patients who received transplants during chronic phase, the poor results seen here in patients administered unmodified marrow stem primarily from increased transplant-related mortality rather than increased relapse risk. The strikingly increased relapse rate associated with the use of T-cell depletion would discourage its use for graft-v-host disease prevention in patients who receive transplants for CML.

Adolescent↗
PubMed1987

Treatment of marrow graft recipients with thymopentin.

Four adult patients with acute non-lymphocytic leukemia were given marrow grafts from HLA-identical siblings following 120 mg/kg cyclophosphamide and 10-12 Gy total body irradiation. All received intermittent intravenous methotrexate as prophylaxis against graft-versus-disease (GVHD). In an attempt to accelerate immune recovery and prevent GVHD, each patient received thymopentin (TP5) for 100 days after grafting. No adverse effects were seen with TP5 administration. All four patients developed acute GVHD (one grade I, one grade II, and two grade III). Two patients died of late infections: one at 6 months from Pneumocystis carinii pneumonia and one at 11 months from disseminate Pseudomonas, Candida and cytomegalovirus infection. Two patients survive more than 3.9 years after transplantation with Karnofsky scores of 100%. One required treatment for chronic GVHD and recovered. Delayed-type hypersensitivity, antibody production to specific antigen in vivo, and results of in vitro immunologic studies were not altered by TP5 treatment. We conclude that while the administration of TP5 in these patients as described was not harmful, it did not prevent opportunistic infection, improve immunologic reconstitution or lower the incidences of acute or chronic GVHD from that of our previous experiences without thymopentin.

Adult↗
PubMed1987

Proliferative and differentiative responses of B cells from human marrow graft recipients to T cell-derived factors.

Upon activation, B cells express growth and differentiation receptors that permit them to proliferate and differentiate. The aim of this study is to define the nature of the intrinsic B cell defects found in marrow recipients using assays for B cell activation, proliferation, and differentiation. B cells from five short-term (less than three months postgrafting) and 15 long-term (greater than one year postgrafting) marrow recipients (ten with and five without chronic graft-v -host disease [GVHD]) were studied. T cell supernatants (T-sup) were prepared by stimulating normal T cells with 12-0-tetradecanoyl-phorbol-13-acetate (TPA) and phytohemagglutinin. Highly purified B cells were used to assess B cell proliferation responses to T-sup after Staphylococcus aureus Cowan I (SAC) activation and for B cell immunoglobulin production responses to T-sup stimulation after SAC activation. B cells from all five short-term patients and one long-term patient with chronic GVHD did not respond to any stimulation. B cells from two patients with chronic GVHD responded to SAC but had decreased proliferative and differentiative responses to T-sup. B cells from three of seven patients with chronic GVHD and two of five long-term healthy patients could proliferate but could not secrete immunoglobulin in response to SAC plus T-sup stimulation. Furthermore, there was a significant correlation between serum IgG and/or IgM in marrow recipients and the differentiative responses of their B cells to T-sup (P = 0.0075, Fisher's Exact). B cell defects occur at various stages of maturation postgrafting. These defects include the failure to respond to the SAC activation signal, the failure to proliferate in response to T-sup, and the failure to differentiate in response to T-sup. These findings are probably due to the inability of B cells from certain marrow recipients to undergo a second round of ontogeny.

Antibody Formation↗
PubMed1986

Regulation of immunoglobulin production after human marrow grafting. The role of helper and suppressor T cells in acute graft-versus-host disease.

The effect of acute graft-versus host disease (GVHD) on T4 and T8 lymphocyte regulation of in vitro immunoglobulin production was explored. The peripheral blood lymphocytes from 20 patients were studied sequentially in the first 100 days after sibling bone marrow grafting for hematologic malignancy or aplastic anemia. T and non-T lymphocytes were prepared from peripheral blood by Ficoll-Hypaque density gradient centrifugation and sheep erythrocyte rosetting. T cells were enriched for T4 or T8 cells and cocultured for six days with pokeweed mitogen and autologous non-T or T and non-T cells from unrelated normal individuals. Immunoglobulin production was assessed using a reverse hemolytic plaque assay. All three patients without acute GVHD had failure of non-T cells to secrete immunoglobulin, one had failure of helper T cell activity, and 2 developed suppressor T cells. Similarly, all six patients studied sequentially after the development of GVHD had non-T-cell failure, five developed helper T cell failure, and five had suppressor T cells. These data suggest no difference in lymphocyte function before or after the development of acute GVHD. When the T cells of these patients were split into T4 and T8 subpopulations and studied for immunoglobulin production there was helper T cell failure in 4 of 9 tests with enriched T4 populations. Five of 9 tests with T8 enriched populations showed suppressor activity. Suppressor T cell function was also seen in 4 of 9 tests with with T4-enriched populations. These data show that T cell function does not necessarily correlate with the surface phenotype during the first 100 days after grafting. A role for cytomegalovirus (CMV) infection in bringing out suppressor activity is suggested, because among patients without GVHD, 6 of 8 tests in CMV-positive patients showed suppressor cells compared with none of 4 tests in patients without CMV infection.

Antibody Formation↗
PubMed1986

Antigen-specific antibody responses of lymphocytes to tetanus toxoid after human marrow transplantation.

In vitro IgG anti-tetanus toxoid (IgG anti-TT) antibody produced by peripheral blood lymphocytes (PBL) from 16 normal subjects (9 marrow donors and 7 random healthy subjects) and 17 marrow graft recipients from 45-1058 days postgrafting was measured with an enzyme-linked immunosorbent assay (ELISA). PBL from 11 of 13 seropositive (anti-TT greater than or equal to 1:1024) normal subjects produced IgG anti-TT in vitro, whereas the PBL from the 3 seronegative (IgG anti-TT less than 1:1024) normal subjects did not. In our normal subjects, there was a high correlation between seropositivity and in vitro IgG anti-TT production (P = .0048, chi 2, two-tailed). PBL from only one of 13 seropositive marrow graft recipients produced in vitro IgG anti-TT antibody. B and T cell functions of 8 marrow graft recipients were assessed by coculturing their T and B cells with those from their HLA-identical marrow donors. One short-term patient and 7 long-term patients (4 with and 3 without chronic graft-versus-host disease) were studied. Recipient B cells failed to produce antibody in the presence of donor T cells in 7 of these 8 cases. However, T cells from long-term survivors provided helper activity to immune donor B cells in 7 of 9 evaluable cases. TT-specific helper T cell activity was present in most seropositive long-term recipients, and B cells from marrow recipients failed to produce specific antibody in the presence of normal donor TT-specific helper T cells. These results, TT-specific T cell helper activity, and normal circulating serum IgG anti-TT antibody levels in marrow graft recipients without postgrafting TT boosters suggest that specific immunity had been transferred from the marrow donor to the marrow recipient.

Adolescent↗
PubMed1986

Myasthenia gravis after allogeneic bone marrow transplantation: relationship to chronic graft-versus-host disease.

Three patients with chronic graft-versus-host disease (GVHD) developed myasthenia gravis (MG) 762 to 1,180 days after allogeneic bone marrow transplantation. Symptoms of MG were observed after taper or discontinuation of immunosuppressive treatment of chronic GVHD. All patients developed antibodies to acetylcholine receptor, and one had antibody formation to striated muscle. One patient died of complications of treatment of MG. The severity of disease underscores the importance of the differential diagnosis and the need for prompt therapy of this late complication after human bone marrow transplantation.

Acetylcholine↗
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

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

Growth and development following marrow transplantation for leukemia.

One hundred forty-two patients between the ages of 1 and 17 years who survived disease-free more than 1 year after marrow transplantation for hematologic malignancy had growth and development evaluations from one to 14 years posttransplant (median 4 years). Prior to transplant all children received multiagent chemotherapy and 55 also received central nervous system irradiation, but none had growth and development evaluations. Marrow transplant preparation included high-dose chemotherapy and total body irradiation (TBI) given as a single dose of 9.2 to 10.0 Gy (79 patients) or as fractionated doses of 2.0 to 2.25 Gy/d for six to seven days (63 patients). After transplant abnormal thyroid function was present in 39%. Stimulated 11-desoxycortisol levels were subnormal in 24% of patients evaluated. Growth hormone (GH) deficiency was present in 17 of 25 children who received previous cranial irradiation. Partial GH deficiency was present in 4 of 25 who received previous cranial irradiation and in 6 of 18 who had not received cranial irradiation. Height velocity was decreased in all patients. After transplant, height was significantly influenced by chronic graft-v-host disease and single-dose TBI. Sixty-eight percent had delayed development of secondary sexual characteristics. Gonadal failure occurred in nearly all who were postpubertal at transplant. While it is not possible to determine how many of these endocrine abnormalities occurred as a result of treatment administered prior to transplantation, these data do demonstrate that children who become long-term survivors after marrow transplantation for hematologic malignancy have endocrine abnormalities that adversely affect growth and development.

Adrenal Cortex↗
PubMed1986

Decreased incidence of marrow graft rejection in patients with severe aplastic anemia: changing impact of risk factors.

Patients with severe aplastic anemia were conditioned with cyclophosphamide (200 mg/kg) and given marrow grafts from HLA-identical family members. Among 233 patients transplanted, 225 survived greater than or equal to 14 days and could be evaluated for engraftment. Forty-four of the 225 rejected their graft; 33 of these died and 11 survive. One hundred eighty-one patients had sustained engraftment; of these, 46 died and 135 survived. Binary logistic regression analyses revealed five risk factors for graft rejection: year of transplant, a large number of platelet transfusions, a positive relative response in mixed leukocyte culture, a low marrow cell dose, and omission of donor buffy coat cell infusion for transfused patients. These data show that patients transplanted recently had a lower likelihood of graft rejection than did patients transplanted in earlier years. Conceivably, this was related to changes in transfusion practices, but other factors as yet unidentified are likely to be involved. The data confirm that the largest possible number of marrow cells should be transplanted. Although the difference in the incidence of graft rejection between untransfused and transfused patients was not significant, it should be noted that transfused patients were given buffy coat cells. Because the addition of buffy coat cells results in a higher incidence of chronic graft-v-host disease (GVHD), it is still desirable to transplant patients with marrow alone early in their course before they have been transfused.

Anemia, Aplastic↗
PubMed1985

Treatment of acute graft-versus-host disease after allogeneic marrow transplantation. Randomized study comparing corticosteroids and cyclosporine.

Seventy-seven patients (age 12 to 46 years) who underwent allogeneic marrow transplantation for hematologic malignancy or aplastic anemia and who had grade II to IV acute graft-versus-host disease despite methotrexate prophylaxis were randomly assigned to receive methylprednisolone 2 mg/kg per day intravenously (n = 39) or cyclosporine (n = 38) either 12 to 15 mg/kg per day orally or 3 to 5 mg/kg per day intravenously. In both groups, clinical and histologic evidence of graft-versus-host disease was detected at medians of 16 and 25 days, respectively. Drugs were given for a minimum of 14 days unless significant deterioration occurred. If graft-versus-host disease did not improve with this therapy, treatment with a second agent was initiated. Treatment responses were scored after reviewing clinical and laboratory data collected before, during, and after the 14-day treatment period. Possible scores were as follows: -1, worse; 0, no change; + 1, improvement in one organ system (skin, liver, gut) with no deterioration in the other two; +2, complete resolution of all involved systems. The median response score among 39 methylprednisolone-treated patients was 0. Sixteen patients (41 percent) showed response to treatment, 11 with partial and five with complete response. The median response score among 38 cyclosporine-treated patients was +1. Twenty-three patients (61 percent) showed response to treatment, 15 with partial and eight with complete response (p = 0.039). Twenty patients receiving methylprednisolone and 18 receiving cyclosporine required additional therapy. The incidence of chronic graft-versus-host disease was similar in both groups. It developed in all nonresponding patients at risk who had received secondary therapy. Among responding patients (scores +1 or +2) who were not given additional treatment, chronic graft-versus-host disease developed in eight of 11 (72 percent) receiving methylprednisolone and five of ten (50 percent) receiving cyclosporine. Survival beyond 17 months was similar in the two groups (28 percent and 24 percent, respectively). These data suggest that cyclosporine is a useful agent for the treatment of acute graft-versus-host disease, comparable in its efficacy to methylprednisolone.

Acute Disease↗
PubMed1985

Donor cell leukemia developing six years after marrow grafting for acute leukemia.

A patient who developed recurrent leukemia more than six years after marrow grafting from an HLA-identical same-sex sibling is reported. Difference in DNA restriction fragment length polymorphisms between donor and host demonstrated that the DNA in the recurrent leukemia sample was probably of donor origin. Possible mechanisms that could explain the long latent period between transplantation and expression of leukemic transformation are discussed. We conclude that future cases of late leukemic recurrence after marrow grafting should be studied to determine whether, in contrast to early relapses, late relapses occur in donor cells in most or all instances.

Adult↗