Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunohistological and morphometric techniques were used to study the skin after marrow transplantation with particular reference to the relationship of marrow purging, the presence of a clinical rash and histological changes to leucocyte numbers and phenotype. Recipients of T-cell-depleted marrow showed significant reductions in CD2+, CD4+ and CD8+ T-lymphocytes in the first 22 d after transplantation but not after this time. T-cell numbers in recipients of unpurged marrow were similar to those of normal donors, indicating a rapid repopulation by cells from the graft. Langerhans cells (CD1+ dendritic cells) and macrophages, on the other hand, were present in similar numbers in both groups of patients within the first 22 d; the former in low and the latter in normal numbers. Biopsies exhibiting graft versus host disease showed increases in CD2+, CD4+ and CD8+ T-lymphocytes with significant lowering of the CD4:CD8 ratio. A proportion expressed markers of activation and HNK1+ cells and macrophages were also increased. Biopsies exhibiting epidermal basal abnormalities only (changes identical to graft versus host disease but without detectable leucocyte infiltration on conventional microscopy) showed a minor increase in macrophages and HNK1+ cells but no other leucocyte alterations to suggest a pathogenetic link with graft versus host disease. Langerhans cells were reduced in these biopsies, however, when taken more than 22 d post-transplant, suggesting that the epidermal changes are associated with Langerhans cell damage or repopulation. We were unable to identify any significant alteration in leucocytes in patients with strong clinical evidence of graft versus host disease but with histologically unremarkable biopsies. Although it is possible that perivascular increases in T-cells and expression of activation markers precede the characteristic histological picture of graft versus host disease the time scale is probably too short to allow diagnostic value.
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PMID:Cutaneous leucocyte composition after human allogeneic bone marrow transplantation: relationship to marrow purging, histology and clinical rash. 328 67

The cellular composition of the spleen has been assessed in 18 patients who died 15-326 days after receiving allogeneic marrow for leukaemia. The white pulp showed marked lymphocyte depletion with no germinal centres, very few B cells, and rare plasma cells. The marginal zone was unrecognizable but there were moderate numbers of T cells in the periarteriolar lymphatic sheaths (PALS), showing great variation in CD4/CD8 ratio. The percentage of CD4+ cells decreased with time post transplant. CD8+ cells were reduced in patients with graft-versus-host disease (GvHD) who also showed no increase in cells staining for activation markers. No T cells were detected expressing immature phenotypes and no differences were detected between patients who received marrow purged or unpurged of T cells. Macrophage numbers appeared normal. Extramedullary haemopoiesis (EMH) was predominantly in the red pulp greater than 30 days after transplantation but more commonly in the white pulp before then. Pyknotic cells were common in seven cases and appeared to be associated with EMH rather than GvHD. Chimaeric studies demonstrated small numbers of donor cells in the PALS at 26 days and larger numbers at 56 days.
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PMID:Cellular composition of the spleen after human allogeneic bone marrow transplantation. 329 36

Sixteen patients with haematological malignancy received high-dose chemotherapy or chemotherapy and total body irradiation followed by an HLA-identical sibling marrow transplant from which the T lymphocytes had been depleted prior to infusion by incubation with an anti-CD2 anti-T cell antibody with (seven patients) or without (nine patients) an anti-CD8 anti-T cell antibody together with rabbit complement. Additionally, all patients received cyclosporin. The number of T cells present in the donor marrow was determined by limiting dilution analysis, and was found to correlate with the subsequent incidence and severity of acute graft-versus-host disease (GVHD). The number of T cells infused into patients with no acute GVHD or with minimal acute GVHD of the skin (skin rash present for 14 days or less) was 1.3 +/- 1.0 x 10(5)/kg, while the number infused into those with moderate acute GVHD or with skin acute GVHD present for 15 days or more was 12.3 +/- 11.5 x 10(5)/kg (p less than 0.001). Thus a dose of 10(5) (or less) T cells/kg was associated with minimal or no acute GVHD, while 10(6) T cells/kg (or more) caused significant disease.
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PMID:Human marrow T cell dose correlates with severity of subsequent acute graft-versus-host disease. 333 57

The IBM 2991 Blood Cell Processor has been used to isolate a mononuclear cell (MNC) fraction from the marrow of 31 allogeneic donors. The MNC fraction was then incubated with a combination of two murine monoclonal antibodies MBG6 (CD6) and RFT8 (CD8) followed by two rounds of treatment with rabbit complement resulting in a marrow inoculum significantly reduced in the number of T-lymphocytes. We report here new specifications for the use of Ficoll-Metrizoate, the method used to calculate T-lymphocyte depletion and the details of our attempts to improve T-depletion. Following marrow transplantation with this T-depleted fraction, 29 patients are evaluable for engraftment, one patient failed to engraft and one died too early for evaluation. Twenty-two had no acute graft-versus-host disease (aGvHD), at a minimum of 60 d, six had grade I acute GvHD and one grade III. No correlation was found between the absolute number of MNC infused and time to engraftment, nor any relationship between the number of residual viable T-lymphocytes in the infused marrow and the incidence of GvHD, but the patient with the most severe aGvHD also had the highest number of T-lymphocytes infused.
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PMID:Standardization of T-cell depletion in HLA matched bone marrow transplantation. 353 Mar 16

Donor lymphocyte infusions can reinduce complete remission in the majority of patients with chronic myelogenous leukemia (CML) who relapse into chronic phase after allogeneic bone marrow transplantation (BMT). Such infusions are associated with a high incidence of graft-versus-host disease (GVHD) and marrow aplasia. BMT using selective depletion of CD8+ lymphocytes from donor cells reduces the incidence of GVHD without an increase in leukemia relapse. We hypothesized that infusion of CD8-depleted donor peripheral blood lymphocytes could also reinduce complete remissions with a lesser potential to produce symptomatic GVHD in patients with CML who relapsed after allogeneic BMT. Ten patients with Ph(+) CML who relapsed a median of 353 days after BMT (range, 82 to 1,096 days) received donor lymphocyte infusions depleted of CD8+ cells. Nine patients received a single infusion and 1 received two infusions. Four patients were treated while in chronic phase with clonal evolution, 2 during accelerated phase, 3 during blast crisis, and 1 in a cytogenetic relapse. A mean of 0.9 +/- 0.3 x 10(8) mononuclear cells/kg were infused, containing 0.6 +/- 0.4 x 10(6) CD3+CD8+ cells/kg. Six patients achieved hematologic and cytogenetic remission at 4, 8, 11, 15, 39, and 54 weeks after lymphocyte infusion. Two patients developed > or = grade II acute GVHD, and 1 patient developed mild chronic GVHD. We conclude that donor lymphocyte infusions depleted of CD8+ cells can induce remissions with a low rate of severe acute GVHD in patients with CML who relapse after allogeneic BMT, supporting the hypothesis that CD8+ lymphocytes are important effectors of GVHD, but may not be essential for the graft-versus-leukemia effect against this disease. Further controlled studies are required to confirm these preliminary observations.
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PMID:CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. 749 95

A new pharmacologic agent, anti-CD3F(ab')2-ricin toxin A chain (RTA), was synthesized for the purpose of targeting T cells and as a means of treating established graft-versus-host disease (GVHD). The Fc region of anti-CD3 monoclonal antibody (MoAb) was removed to prevent its ability to activate T cells. The resulting F(ab')2 fragments were conjugated to deglycosylated RTA (dgRTA), a catalytic and potent phytotoxin. The resulting immunotoxin (IT) was potent (greater than 95% inhibition) and selective in inhibiting T-cell mitogenesis in vitro. In vivo, the IT depleted 80% of T cells in mice receiving bone marrow (BM) transplants. Transplantation in an aggressive acute GVHD model using C57BL/6 donor cells and H-2 disparate B10.BR recipients resulted in an infiltration of CD3-expressing cells and a median survival time (MST) of 20 to 30 days. A 5-day course of anti-CD3F(ab')2-RTA (30 micrograms/d intraperitoneally) beginning 7 days after GVHD induction was beneficial in treating established GVHD in these mice, as evidenced by significantly prolonged survival (MST, greater than 80 days), superior mean weight values, and improved clinical appearance. Neither intact anti-CD3, unconjugated anti-CD3 F(ab')2 fragments, nor a mixture of anti-CD4 and anti-CD8 MoAbs (which are highly effective in prophylactic models) were as effective. F(ab')2 fragments made from anti-Lyt-1 (the murine homologue of human anti-CD5) linked to RTA were also not effective, despite the fact that both anti-CD3F(ab')2-RTA and anti-Lyt-1F(ab')2-RTA had similar half-lives of about 9 hours. The IT also increased MST in two aggressive models of GVHD across non-H-2 minor histocompatibility barriers, indicating that the usefulness of anti-CD3F(ab')2-dgRTA is not limited to a single-strain combination. This agent should be further investigated as an alternative to current strategies for treating steroid refractory GVHD.
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PMID:Therapy for ongoing graft-versus-host disease induced across the major or minor histocompatibility barrier in mice with anti-CD3F(ab')2-ricin toxin A chain immunotoxin. 749 98

Peripheral blood lymphocytes (PBL) from 24 allogeneic bone marrow transplant (BMT) recipients were studied serially using flow cytometry and two-color analysis. Dual labelling with two monoclonal antibodies (moAbs), CD8/S6F1 (CD11a) and CD8/CD57 was used to analyze the surface phenotypes of PBL after allogeneic BMT. In patients with acute and chronic GVHD, CD8+S6F1+ cells were markedly increased from the onset of GVHD and recovered to normal range 6 years after transplantation. By contrast, CD8+S6F1- cells fell below normal range and remained markedly decreased for 2-3 years after transplantation in patients with acute and chronic GVHD. A slight but significant increase of CD8+CD57- cells was observed with clinical signs of acute GVHD. On the other hand, CD8+CD57+ cells were increased after the onset of acute and chronic GVHD and recovered to normal range 6 years after transplantation. These results suggest that these subsets of CD8+ cells may play important roles in the pathophysiology of GVHD.
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PMID:Marked increase of CD8+S6F1+ and CD8+CD57+ cells in patients with graft-versus-host disease after allogeneic bone marrow transplantation. 751 41

The effects of rhG-CSF on peripheral blood lymphocytes and lymphocyte populations in the apheresis product has been determined in 13 individuals (11 autografts and 2 normal donors) who had peripheral blood mononuclear cells (PBMCs) collected on days 3, 4, and 5 of administration of rhG-CSF 16 micrograms/kg/day x 5 days. The absolute number of CD34+ cells increased 9 and 25-fold from pretreatment levels after 4 and 5 days of rhG-CSF, respectively. All patients demonstrated an increase in CD3, CD4, CD8, CD19 and CD20 lymphocytes after 3 days of rhG-CSF with T lymphocytes increasing 1.5-2.0 times baseline by day 3 or rhG-CSF administration. All lymphocyte phenotypes returned to below pretreatment levels on days 4 and 5 of rhG-CSF administration. The ratio of CD4/CD8 lymphocytes was not affected by rhG-CSF. Collection of PBMCs on 3 consecutive days yielded a mean of 8.77 x 10(8) CD34 cells, 14.03 x 10(10) total nucleated cells and 3.17 x 10(10) CD3 lymphocytes. These data suggest that rhG-CSF mobilized PBMCs have approximately one log more T cells than marrow and the effect of rhG-CSF on the quantity and phenotype of lymphocytes is minimal. Strategies for coping with an increased incidence of GVHD, if it occurs, could include the utilization of both methotrexate and cyclosporine as immunoprophylaxis, selective T cell depletion or CD34 positive selection.
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PMID:Lymphocyte content in peripheral blood mononuclear cells collected after the administration of recombinant human granulocyte colony-stimulating factor. 751 58

Patients who receive bone marrow transplants from unrelated donors have a high incidence of graft-versus-host disease (GVHD). If the donor marrow is first T cell-depleted, the everity of GVHD declines but the risk of rejection rises. In an attempt to prevent both graft rejection and GVHD, we included an anti-T cell antibody-toxin conjugate (CD-5-Ricin; XomaZyme H65) in the transplant conditioning regimen. After receiving a partially T cell-depleted marrow, patients then received a second course of immunotoxin as additional GVHD prophylaxis. Eight recipients of unrelated donor marrow transplants were studied. All engrafted (ANC > 500 x 10(6)/l by day 15, range 13-20 days). One patient had grade II skin GVHD and one developed grade IV disease but the other six patients had no acute GVHD. However, there was high morbidity and mortality from virus infections associated with a sluggish return of CD4 and CD8 T cells into the normal range. Four patients died from virus disease (CMV, n = 2; EBV, n = 1; adenovirus, n = 1) and the remaining patients had frequent documented viral illnesses during the first year. We conclude that improvement in the outcome of unrelated donor marrow transplantation will require strategies which prevent rejection and GVHD coupled with attempts to accelerate immune reconstitution.
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PMID:XomaZyme-CD5 immunotoxin in conjunction with partial T cell depletion for prevention of graft rejection and graft-versus-host disease after bone marrow transplantation from matched unrelated donors. 751 37

Prevention of graft-versus-host disease by depletion of CD6-positive T cells was studied in the dog. Donors were DLA-homozygous, recipients DLA-heterozygous with one DLA haplotype identical to the donor. Seven control dogs received untreated marrow and died of GvHD after full hemopoietic recovery within 28 days of transplantation. For prevention of GvHD, immunomagnetic separation of T cells with a monoclonal antibody against human CD6 that crossreacted with canine T cells was evaluated. Depletion of CD6-positive cells depleted CD4-positive cells completely, but only part of CD8-positive cells and DR-positive cells. CD6-depleted marrow exhibited strong nonspecific "natural" suppression of the generation of cytotoxic T cells in vitro. Eleven dogs received CD6-depleted marrow. Only 1 dog developed GvHD and died. Sustained engraftment was seen in 8 dogs. Hemopoietic recovery was delayed and slower after transplantation of CD6-depleted marrow than after transplantation of untreated marrow. Four of these dogs were treated with G-CSF, and this accelerated the recovery of leukocytes, but did not prevent rejection. Chimerism was mixed in 7 of 10 evaluable dogs and 1 dog recovered its own hemopoiesis 2 years after transplantation. CD6 depletion prevents GvHD across a DLA-haplotype difference, but rejection and mixed chimerism may occur. Treatment with G-CSF accelerates leukocyte recovery, but cannot prevent rejection.
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PMID:Prevention of graft-versus-host disease in DLA-haplotype mismatched dogs and hemopoietic engraftment of CD6-depleted marrow with and without cG-CSF treatment after transplantation. 752 57


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