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

In the present study, we examined changes in the expression of CD45RA, CD31, and CD29 on total CD4 and CD8 lymphocytes in patients who had received CD6 T cell-depleted allogeneic marrow and received no immune suppressive drugs after engraftment in order to identify defects in reconstitution of immunoregulatory T cells after allogeneic BMT. Results following allo-BMT were compared with normal controls and patients following autologous BMT. We showed that CD4+CD45RA+, CD4+CD29+ (CD29high), and CD4+CD31+ cells were markedly decreased during the first 24 months after allo- and auto-BMT. CD8+CD45RA+ cells recovered to normal levels within the first month after auto-BMT, while after allo-BMT, the CD8+CD45RA+ cells were at slightly low levels during the first month, but gradually increased to normal levels by 12 months post-BMT. CD8+CD29+ cells were increased during the first 12 months both after allo- and auto-BMT although during the first month, a decreased percentage of CD8+CD29+ cells was observed in allo-BMT patients. More important, CD4+CD29+, CD8+CD29+, and CD8+S6F1+ cells were significantly increased in patients with moderate-to-severe acute GVHD (grades II-IV) compared with those with or without mild acute GVHD (grade I), suggesting that CD4 helper-inducer (CD4+CD29high) and CD8 killer-effector (CD8+CD29highS6F1+) cells play an important role in the pathophysiology of acute GVHD.
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PMID:The phenotype and reconstitution of immunoregulatory T cell subsets after T cell-depleted allogeneic and autologous bone marrow transplantation. 791 Sep 87

Forty-eight adult leukemic recipients of HLA-identical sibling marrow were randomized to T cell depletion using anti-CD8 and anti-CD6 antibodies plus complement (n = 28) or prophylaxis with methotrexate (MTX) and cyclosporine (CsA) (n = 25). Patient characteristics were comparable in the two groups. The median observation time was 5 1/2 years. Transfusions, infections, and acute GVHD did not differ between the groups. Chronic GVHD occurred in 52% of patients receiving T cell-depleted marrow and 23% of those receiving MTX + CsA (P = 0.06). Overall probability of relapse was similar in both groups and actuarial leukemia-free survivals at 5 years were 39% and 35% in the two groups, respectively. Among patients with chronic myeloid leukemia (CML), leukemia-free survival at 5 years was 25% in patients receiving T cell-depleted marrow compared with 51% in those given MTX + CsA (P = 0.09). In patients with acute leukemia the probability of relapse was 24% in the group receiving T cell-depleted marrow compared with 73% in those treated with MTX + CsA (P = 0.06). Leukemia-free survival was 55% and 21% in the two groups, respectively (NS). CML patients tended to have a poorer prognosis and those with acute-leukemia better outcome with T cell depletion than with combined MTX + CsA. It is concluded that T cell depletion is unsuitable for patients with CML, but may be considered in patients with acute leukemia.
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PMID:Long-term follow-up of a randomized trial comparing T cell depletion with a combination of methotrexate and cyclosporine in adult leukemic marrow transplant recipients. 794 Jul 31

T-cell depletion of donor bone marrow has been associated with an increased risk of disease relapse after allogeneic bone marrow transplantation (BMT). Recombinant interleukin-2 (IL-2), which is capable of increasing the antileukemic activity of peripheral blood lymphocytes obtained from patients who have undergone BMT, has been proposed as a potentially useful agent to reduce the risk of relapse post-BMT. We have previously shown that IL-2 administered to patients at very low doses after BMT is both clinically tolerable and immunologically active. We now report on the clinical outcome of 29 patients treated with low-dose IL-2 after CD6-depleted allogenic BMT for hematologic malignancy. IL-2 was administered by continuous infusion for up to 3 months beginning at a median of 67 days post-BMT. Eligibility requirements for IL-2 therapy included demonstration of stable engraftment and absence of acute grade 2-4 graft-versus-host disease (GVHD). Low-dose IL-2 was well tolerated by the majority of patients, with only 4 of 29 subjects withdrawn early. Acute GVHD developed in only one individual. After 12 weeks of treatment, the mean number of circulating natural killer cells in patients increased 10-fold without any significant change in T-cell number. Of the 25 patients who received > or = 1 month of IL-2, only 6 have relapsed. Relapse rate and disease-free survival (DFS) were determined in the 25 patients who completed at least 4 weeks of IL-2 treatment and compared with historical controls transplanted at our institution for the same conditions and treated with an identical ablative regimen and method of T-cell depletion. Only control patients who had survived disease free for 100 days post-BMT were included in this analysis. Cox's proportional hazards regression model suggested that, compared with control patients without a history of GVHD, patients treated with IL-2 had a lower risk of disease relapse (hazard ratio 0.34; range, 0.14 to 0.82) and superior DFS (hazard ratio 0.39; range 0.18 to 0.87). A randomized controlled trial of IL-2 immunotherapy after T-cell-depleted BMT should now be undertaken.
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PMID:Effect of low-dose interleukin-2 on disease relapse after T-cell-depleted allogeneic bone marrow transplantation. 804 78

Acute and chronic graft-versus-host disease (GVHD) are responsible for a significant fraction of the morbidity and mortality of allogeneic bone marrow transplantation. Attempts to reduce the incidence of GVHD by exhaustive T cell depletion of donor marrow have frequently been associated with an increase in graft failure and disease relapse. For the past 10 years, we have evaluated the use of a monoclonal antibody (T12) that selectively targets the CD6 determinant on mature T cells. 171 patients with hematologic malignancies have received donor marrow depleted of mature T cells with anti-CD6 and rabbit complement. Initial engraftment in recipients of HLA-matched marrow has been > 98% with 96% of patients showing stable hematologic reconstitution. The incidence of acute GVHD in this population was only 15%. Chronic GVHD has developed in 5% of patients. Overall, transplant-related mortality was 17%. Examination of peripheral blood lymphocyte reconstitution in the early post-BMT period has been helpful in predicting which patients will ultimately go on to develop GVHD. Treatment of recipients of CD6 depleted marrow with low doses of interleukin-2 post-BMT can expand the number of circulating NK cells and may be associated with a decrease in disease relapse rate.
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PMID:Selective T cell depletion of donor allogeneic marrow with anti-CD6 monoclonal antibody: rationale and results. 812 62

We report the development of a potent anti-pan T-cell immunotoxin capable of killing cells in an antigen dependent manner. The immunotoxin is composed of a high affinity anti-CD6 antibody (IgG2a, Kd = 1.3 x 10(-11) M) conjugated to blocked ricin that is a chemically modified ricin molecule wherein the lectin binding sites of the B-chain have been blocked by covalent attachment of affinity ligands. Conjugation of blocked ricin to the antibody has minimal effect on the apparent affinity of the antibody and no effect on the ribosome-inactivating activity of the ricin A-chain moiety. Anti-CD6-blocked ricin is a specific and highly toxic immunoconjugate killing the antigen-positive Molt-4 cell line with an IC37 of 4 x 10(-12) M after a 24 h exposure of cells to the immunotoxin. Nonspecific cytotoxicity of anti-CD6-blocked ricin for the antigen-negative Namalwa cell line was more than 750-fold lower with an IC37 > 3 x 10(-9) M. The cytotoxicity of anti-CD6-blocked ricin is dependent on the length of the incubation of cells with the conjugate ranging from an IC37 of 1.5 x 10(-11) M leaving a surviving fraction of Molt-4 cells of 0.03 after a 2.5 h exposure to an IC37 of 5 x 10(-13) M and leaving a surviving fraction of 3 x 10(-6) after a continuous (3 weeks) exposure. Anti-CD6-blocked ricin is also capable of killing CD6 positive cells in human peripheral blood lymphocyte populations. Systemic toxicity of anti-CD6-blocked ricin in mice is similar to the toxicity of other immunotoxins containing blocked ricin that were found to be tolerated well by patients. An application of this immunoconjugate for the prevention and treatment of graft versus host disease or tissue graft rejection is suggested.
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PMID:Anti-CD6-blocked ricin: an anti-pan T-cell immunotoxin. 815 May 54

The appropriate timing of bone marrow transplantation (BMT) for adults with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) is controversial. Although allogeneic transplantation results in a lower risk of disease recurrence than intensive chemotherapy alone, overall outcome following BMT may not be improved due to the higher incidence of therapy-related fatal complications, frequently as a result of the development of graft-versus-host disease (GVHD). Selective T-cell depletion of donor marrow can reduce the incidence of GVHD and thereby limit transplant-related toxicity. Herein we report the risk of GVHD, incidence of transplant related mortality (TRM), likelihood of disease relapse, and overall survival in adult patients undergoing BMT with CD6 depleted allogeneic marrow for acute leukemia in first remission. Forty-one consecutive allogeneic transplants were performed on patients with acute leukemia and high-risk features (28 AML, 13 ALL) using T12 monoclonal antibody and complement to remove CD6+ T cells from donor marrow. No pre- or posttransplant immune suppressive medications for GVHD prophylaxis were administered. The actuarial estimated risk of grade 2 to 4 acute GVHD was 15% in patients receiving HLA identical grafts. Chronic GVHD developed in five patients. The estimated risk of TRM for patients in first complete remission was 5% at Day +100 and 16% at 2 years. Fatalities attributable to infection with cytomegalovirus or Epstein-Barr virus occurred in only three patients. Estimated probabilities of relapse, overall survival, and event-free survival at 4 years were 25%, 71%, and 63%, respectively. No significant differences in GVHD, TRM, relapse rate, or survival was observed for patients with AML compared with those with ALL. Allogeneic transplantation with CD6 depleted bone marrow is effective in consolidating remissions of high-risk patients with acute leukemia in first remission without excessive toxicity.
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PMID:CD6-depleted allogeneic bone marrow transplantation for acute leukemia in first complete remission. 910 25

The widespread use of allogeneic bone marrow transplantation (BMT) is limited by the availability of suitable donors. Recent attempts to expand the donor pool by employing HLA matched unrelated marrow have been partially successful. However, severe graft-versus-host disease (GVHD) and graft failure remain obstacles and contribute to the substantial morbidity and mortality associated with matched unrelated BMT. The use of genotypically nonidentical related or unrelated donor marrow could have wider application if problems associated with GVHD could be overcome. Based upon the low incidence of GVHD in recipients of HLA-matched related donor marrow depleted of T cells with T12, an anti-CD6 monoclonal antibody, we applied this approach to 27 adult recipients of HLA mismatched related bone marrow. Ten patients received marrow mismatched at 2 HLA loci, 13 received 1 antigen mismatched marrow, and 4 received phenotypically identical marrow from a non-sibling. Immediately prior to admission, patients were treated with total lymphoid irradiation (750-1050 cGy) to suppress host derived. T lymphocytes capable of mediating graft rejection. The ablative regimen consisted of cyclophosphamide (60 mg/kg x 2 days) followed by total body irradiation (1400 cGy in 7 fractions over 4 days). Patients then received marrow depleted of T cells with T12 (CD6) plus complement. No immune suppressive medications were administered to prevent GVHD. Twenty-four of 27 patients displayed stable hematologic engraftment, achieving an absolute neutrophil count of 0.5 x 10(9)/L at a median of 19 days post-BMT. Degree of HLA disparity did not influence engraftment. Among engrafting patients, grades 2-4 acute GVHD occurred in 40% and grade 3-4 GVHD in 8%. Chronic GVHD developed in 5 patients. Patients mismatched at 2 loci were more likely to develop GVHD than those mismatched at 0-1 loci (logrank, p = .04). Disease relapse has occurred in only 3 patients receiving mismatched marrow. Estimated overall survival for mismatched patients is 56% at 2 years and is independent of HLA disparity. Among the patients transplanted for chronic myelogenous in stable phase or acute leukemia in first remission, estimated event free survival is 69% at 2 years compared to 20% for patients with more advanced disease. Our results suggest that transplantation of mismatched related marrow using modalities designed to reduce GVHD without immune suppressive medication (CD6 depletion) is feasible and should prompt wider investigation into the extended families of patients in the search for potential marrow donors. This approach also merits investigation in recipients of matched unrelated marrow as a potential means of reducing transplant-related toxicity.
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PMID:CD6+ T cell depleted allogeneic bone marrow transplantation from genotypically HLA nonidentical related donors. 920 36

For patients with non-Hodgkin's lymphoma (NHL) undergoing blood or bone marrow transplantation (BMT), the use of autologous grafts has often been preferred to that of allogeneic stem cells because of a significantly lower incidence of non-relapse mortality. If complications associated with allo-BMT could be minimized without compromising efficacy, then it might become a preferred strategy for certain subsets of patients. In this report, we describe the toxicity and long-term efficacy of T cell-depleted allogeneic BMT using anti-CD6 monoclonal antibody and complement alone to reduce the risk of GVHD and its sequelae. Twenty-two patients, aged 18-60 years, with high (n = 10), intermediate (n = 9), or low (n = 3) grade NHL underwent HLA-identical allogeneic BMT from siblings. Patients had either relapsed after at least one remission or never achieved a full remission with chemotherapy. Twenty patients had a history of marrow involvement. Bone marrow was depleted of CD6+ T cells with T12 monoclonal antibody and complement as the sole form of GVHD prophylaxis. Stable hematopoietic engraftment occurred in all 22 patients. Four patients developed grade 2 and 1 patient grade 3 GVHD (23% grades 2-4 GVHD). Chronic GVHD has occurred in three patients. Treatment-related mortality was very low. Only one patient died while in remission. Thirteen patients are alive and free of disease with a median follow-up of 30 months. Estimated event-free and overall survivals are 54 and 59%, respectively. CD6 allogeneic marrow transplantation is associated with a low risk of transplant-related complications and may offer advantages for certain patients with recurrent NHL felt to be at high risk for relapse after autologous transplantation.
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PMID:CD6+ T cell-depleted allogeneic bone marrow transplantation for non-Hodgkin's lymphoma. 967 48

Hematopoietic growth factors have shown clinical benefits in patients undergoing chemotherapy and stem cell transplantation, but few studies have been performed to assess whether the benefits are worth the costs. We reviewed 196 patients undergoing T-cell depleted related donor bone marrow transplantation (BMT) between 1990 and 1996 to assess the effect of growth factor use on time to engraftment and costs of hospitalization. Beginning in 1994, based on encouraging results in autologous transplantation, patients (n = 81) were treated with granulocyte colony-stimulating factor (G-CSF) starting at day +1 after marrow infusion until engraftment. Between January 1, 1990 and January 1, 1994, patients (n = 115) did not receive growth factor. CD6 depletion of donor marrow was the only form of prophylaxis against graft-versus-host disease (GVHD). Despite receiving a lower stem cell dose (P = .004), the group receiving G-CSF had a decreased time to engraftment (20 days v 12 days, P < .0001) and time from marrow infusion to discharge (23 days v 17 days, P < .0001). In multivariate modeling, the use of G-CSF was the most significant factor predicting time to engraftment and discharge. Incidence of grades II-IV GVHD, early mortality, percentage of patients who engrafted, and relapse rates did not differ between the groups. Inpatient charges during the first 50 days after marrow infusion (including readmissions) were available on 110 patients and were converted to costs using departmental ratios of costs of charges. Median costs were significantly lower in the group receiving G-CSF ($80,600 v $84,000, P = .0373). Thus, use of G-CSF in this setting allows earlier hospital discharge with lower costs.
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PMID:Efficacy and costs of granulocyte colony-stimulating factor in allogeneic T-cell depleted bone marrow transplantation. 976 56

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of hematopoiesis due to a mutation in the PIG-A gene. Affected patients may demonstrate hemolysis or venous thrombosis, and may develop MDS or aplastic anemia. Successful results may be obtained after conditioning and transplantation from syngeneic or genotypically matched sibling donors. Experience with transplantation from matched unrelated donors (MUD) is limited to eight patients, with only one survivor. We report three patients who underwent successful MUD BMT for PNH. All three patients had severe aplastic anemia (SAA) and PNH at the time of BMT. Unrelated donors were six-antigen HLA-matched (n = 2) or HLA-A mismatched (n = 1). Conditioning consisted of cytarabine, cyclophosphamide, TBI, and ATG. Grafts were T cell-depleted by anti-CD6/CD8 antibodies + complement. Further GVHD prophylaxis consisted of cyclosporine. Patients received 0.7-1.1 x 10(8) nucleated cells/kg and 1.1-2.1 x 10(6) CD34(+) cells/kg. Neutrophil engraftment occurred at 16-21 days. One patient developed grade 1 acute GVHD. Although all three patients experienced significant transplant-related complications, they ultimately resolved and all patients are alive and well 30-62 months after BMT. T cell-depleted MUD BMT is an effective treatment option for PNH-related MDS and SAA.
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PMID:Successful unrelated donor bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. 1131 87


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