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)

B cells appear to play a role in chronic graft-versus-host disease (cGVHD) as shown in murine models and the success of anti-CD20 B cell antibody treatment in humans. Recent studies have shown that immunostimulatory microbial CpG-DNA splenic responses were enhanced in murine GVHD. We hypothesized that CpG-induced B cell responses are increased in human cGVHD. Newly diagnosed cGVHD patients enrolled on the COG protocol ASCT0031 were divided into early (3-8 months postblood and marrow transplant [BMT]) and late (> or =9 months post-BMT) onset groups and compared to time-matched control BMT patients. A significantly greater percentage of phosphorothioate (PS)-modified CpG stimulated B cells from cGVHD patients demonstrated an increased expression of CD86 compared to controls (P = .0004). This response had a significant correlation between B cell TLR9 expression (r(2) = 0.65; P = .002) and CD86 upregulation using the entirely TLR9-dependent native phosphodiester CpG (P = .003). The PS-modified CpG response at 2 months after initiation of cGVHD therapy demonstrated a trend toward predicting therapeutic response at 9 months post-BMT (P = .07). These findings suggest that an increased number of B cells, primed for a TLR9 response, may play a role in the pathophysiology of cGVHD.
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PMID:Altered Toll-like receptor 9 responses in circulating B cells at the onset of extensive chronic graft-versus-host disease. 1738 46

Sclerodermatous graft-versus-host disease (GVHD) is a rare complication of bone marrow transplantation. While GVHD is often associated with the beneficial graft vs. tumour effect, it also contributes towards significant morbidity and mortality. No reliably effective treatment has yet been established. We present 10 patients with haematological malignancies who underwent an allogeneic stem cell transplant and developed sclerodermatous GVHD. Donor lymphocyte infusion administered for relapse or reducing donor T-cell chimerism was a known trigger for sclerodermatous GVHD in four of the patients. Treatment with immunosuppressants, psoralen plus ultraviolet A (PUVA) and extracorporeal photopheresis has been largely unsuccessful in their management. Intensive immunosuppression including the use of anti-CD20 monoclonal antibody may have contributed to relapse of leukaemia in one patient 10 years after her transplant. Sclerodermatous GVHD may occur without a preceding lichenoid stage. Clinical heterogeneity is common, although sclerodermatous GVHD has a predilection for the limbs. Treatment options are largely unsatisfactory if conventional immunosuppression fails. PUVA may give some symptomatic benefit and extracorporeal photopheresis seems to be less efficacious than previously published work suggests.
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PMID:Sclerodermatous graft-versus-host disease: clinical spectrum and therapeutic challenges. 1741 93

Paraneoplastic pemphigus is an autoimmune bullous skin disease induced by underlying malignant or benign neoplasias. The diagnostic and immunological criteria of the disease were characterized by Anhalt et al. in 1990. Clinical symptoms are variable, consisting of polymorphous blistering skin eruption and severe, painful mucocutaneous ulcerations. In a subset of patients, only papular lesions develop, resembling lichen planus, or graft-versus-host disease; in some cases blisters may develop later. Severe dyspnea, progressive respiratory failure with clinical features of bronchiolitis obliterans is a rather frequent and severe complication. The diagnosis can be established with direct and indirect immunofluorescent studies and immunoblot analysis. The autoantigens identified to date include cytoplasmic proteins of the plakin gene family: envoplakin (210 kD), periplakin (190 kD), plectin (approximately 500 kD), desmoplakin I (250 kD), desmoplakin II (210 kD) and bullous pemphigoid antigen 1 (230 kD). The desmosomal cadherins: desmogleins 1 and 3, and desmocollins 2 and 3, as well as bullous pemphigoid antigen 2 (180 kD) and an undetermined 170-kD transmembranous antigen are also target autoantigens in the disease. The mortality rate is more than 90 percent. Beside treatment of the underlying tumor, a combination of systemic steroids with immunomodulators, cytostatic drugs, plasmapheresis, plasma exchange, intravenous gammaglobulin, or anti-CD20 monoclonal antibody (rituximab) may be the most appropriate treatment.
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PMID:[Paraneoplastic pemphigus]. 1751 51

The anti-CD20 chimaeric monoclonal antibody Rituximab has recently been shown to induce significant clinical response in a proportion of patients with refractory chronic graft-versus-host disease (cGVHD). We now report 38 patients, median age 48 years (22-61), receiving Rituximab for refractory cGVHD, assessed for clinical response and survival. Median duration of cGVHD before Rituximab was 23 months (range 2-116), the median number of failed treatment lines was 3 (range 1 to > or =6) and the median follow-up after Rituximab was 11 months (1-88). Overall response rate was 65%: skin 17/20 (63%), mouth 10/21 (48%), eyes 6/14 (43%), liver 3/12 (25%), lung 3/8 (37.5%), joints 4/5, gut 3/4, thrombocytopaenia 2/3, vagina 0/2, pure red cell aplasia 0/1 and, myasthenia gravis 1/1. During the study period 8/38 died: causes of death were cGVHD progression (n=3), disease relapse (n=1), infection (n=3), sudden death (n=1). The actuarial 2 year survival is currently 76%. We confirm that Rituximab is effective in over 50% of patients with refractory cGVHD and may have a beneficial impact on survival.
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PMID:Treatment of refractory chronic GVHD with rituximab: a GITMO study. 1803 34

An update is provided on monoclonal antibodies (MAbs): concept, production, indications for the diagnosis and treatment of neoplastic diseases and autoimmune disorders, prevention of transplant rejection, and treatment of allergic diseases, autoimmune disease and other noninflammatory disorders such as coronary disease. Mention is also made of MAb use in the prevention of respiratory syncytial virus (RSV) infection. A more extensive account is provided of the use of MAb in B cell lymphomas (anti-CD20) and T cell leukemias (anti-IL-2 R). Likewise, mention is made of the use of MAbs in autoimmune disorders, such as anti-TNF-alfa in application to chronic arthritis, Crohn's disease and psoriasis, anti-C5 in the treatment of chronic arthritis, uveitis, systemic lupus erythematosus, and autoimmune hemolytic anemia. Anti-KT 3 MAb is used to treat acute rejection and graft versus host disease, while anti-IL-2 R alfa and anti-IL-2 R gamma are used for the prevention of acute transplant rejection. Anti-IgE MAb (omalizumab) is used to treat asthma and allergic rhinitis refractory to other treatments. Anti-L5 (mepolizumab), anti-IL-4, anti-TNF and anti-inflammatory cytokine mediator MAbs all have indications in asthma and severe allergic rhinitis, and in intense atopic dermatitis refractory to other treatments. As to the MAbs used for the prevention of RSV infection, mention is made of anti-epitope A of the F protein of the virus.
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PMID:Monoclonal antibodies in pediatrics: use in prevention and treatment. 1766 23

We describe the clinical course of a patient who experienced refractory pure red cell aplasia (PRCA) after undergoing HLA-matched allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for refractory anemia with an excess of blasts in transformation that had evolved from Kostmann syndrome. The treatment for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) developing from Kostmann syndrome has not been standardized. We treated this patient with allo-PBSCT using a regimen combining high-dose cytosine arabinoside with granulocyte colony-stimulating factor, in addition to total body irradiation and cyclophosphamide without preceding intensive chemotherapy. The donor was ABO incompatible. Myeloid and platelet recoveries were achieved rapidly. Erythroid engraftment was not evident, however, and the patient was given a diagnosis of PRCA. Regimen-related toxicity and graft-versus-host disease (GVHD) were limited. The PRCA did not respond to various therapies, including the discontinuation of immunosuppressants for the induction of chronic GVHD, human recombinant erythropoietin, immunosuppressive treatment with steroids, cyclosporin A, and human anti-CD20 antibody (rituximab). The patient received transfusions 48 times until the resolution of his anemia by donor leukocyte infusion (DLI) at 25 months after PBSCT. He is now clinically well (performance status, 100%) with normal blood cell counts at 5 years after SCT. An in vitro study demonstrated that serum from the recipient blocked the differentiation of erythroid cells in the bone marrow. The results indicate that the conditioning regimen we describe seems safe and effective for those who have MDS/AML and that DLI might be a valuable approach for refractory PRCA after ABO-incompatible SCT.
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PMID:The effect of donor leukocyte infusion on refractory pure red blood cell aplasia after allogeneic stem cell transplantation in a patient with myelodysplastic syndrome developing from Kostmann syndrome. 1819 14

Chronic graft-versus-host disease is a serious complication in long-term survivors of allogeneic hematopoietic stem cell transplantation, with several organ systems affected. Chronic graft-versus-host disease is an important cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. This article reviews the pathogenesis of chronic graft-versus-host disease. In particularly, the role of B cells in chronic graft-versus-host disease is evaluated, as is evident from several studies which have investigated the presence of antibodies as well as studies which have analyzed B cells as a target for immunotherapy. Thirty autoantibodies and 5 alloantibodies have been identified in chronic graft-versus-host disease patients in 24 studies, and 8 autoantibodies and 5 alloantibodies seemed to be strongly associated with chronic graft-versus-host disease. In addition, various studies have observed significant improvements in chronic graft-versus-host disease using the anti-CD20(+) antibody rituximab. However, it appears to be highly likely that both B cells as well as T cells are of major importance in chronic graft-versus-host disease. Further research is required to clarify the pathogenesis of chronic graft-versus-host disease.
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PMID:B-cell involvement in chronic graft-versus-host disease. 1872 20

Rituximab, an anti-CD20 chimeric monoclonal antibody, is widely used in hematologic malignancies and has been introduced as a therapeutic option in autoimmune disorders. In recent studies, rituximab has shown promising activity in steroid-refractory chronic graft-versus-host disease (cGvHD) at a weekly dose of 375 mg/m2. We now report on 13 subjects after peripheral blood stem-cell transplantation receiving low-dose rituximab (50 mg/m2) for steroid-refractory cGvHD and autoimmune disorders (membranous glomerulonephritis and immune thrombocytopenic purpura). The overall response rate was 69%, including two patients with complete responses. In accordance, we observed clearance of peripheral blood B cells even after the first dose of rituximab in four patients. We conclude that low-dose rituximab seems to be active and safe in intensively pretreated patients with steroid-refractory cGvHD.
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PMID:Treatment of chronic steroid-refractory graft-versus-host disease with low-dose rituximab. 1881 13

EBV-induced post transplant lymphoproliferative disorder (PTLD) continues to be a major complication after transplantation. Between January 1993 and April 2006, 12 cases of B-cell lymphoproliferative disorder were identified among 577 patients after allogeneic hematopoietic SCT (HSCT) with an overall incidence of 2.51% at 1 year. Grades II-IV acute GVHD, CMV antigenemia and the use of antithymocyte globulin (ATG) were independent risk factors for PTLD. At diagnosis, all of the tumors were CD20-positive and 11 (92%) were EBV-encoded RNA (EBER)-positive. Of the 12 patients with B-cell lymphoproliferative disorder, 8 had pulmonary involvement and 10 had extranodal involvement. Eleven patients received weekly rituximab therapy at a dose of 375 mg/m(2); the median interval between the onset of symptoms and rituximab therapy was 6 days. The overall mortality rate was 92% and seven (64%) of the deaths were directly attributable to disseminated PTLD within days or weeks of presentation. In our series, pulmonary PTLD followed an extremely aggressive course and poor response to current therapy, even though rituximab was included in the therapeutic regimens.
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PMID:Poor outcome in post transplant lymphoproliferative disorder with pulmonary involvement after allogeneic hematopoietic SCT: 13 years' experience in a single institute. 1883 88

Donor lymphocyte infusions (DLIs) after allo-SCT displayed limited use in CLL and highly malignant non-Hodgkin's lymphoma (NHL). Here we studied whether Bi20 (FBTA05), a novel trifunctional bispecific antibody targeting CD20 on lymphoma cells and CD3 on T cells, could induce GVL responses in combination with DLI or mobilized PBSCT after allogeneic transplantation in these diseases. Six patients (three cases with p53-mutated CLL and three with high-grade NHL (HG-NHL)) refractory to standard therapy were treated with escalating doses of Bi20 (range 10-2000 microg) followed by DLI or SCT. Thereby, all CLL patients showed a prompt but transient clinical and hematological response. In one patient with HG-NHL, we observed a halt in progression for almost 4 months. Side effects (fever, chills and bone pain) were tolerable and appeared at antibody dose levels between 40 and 200 microg. The cytokine profile was characterized by transient increases of IL-6, IL-8 and IL-10. Neither human anti-mouse antibodies nor GVHD developed, allowing repeated treatment courses. In summary, the trifunctional antibody Bi20 induced prompt antitumor responses in extensively pretreated, p53-mutated alemtuzumab and rituximab refractory patients indicating its therapeutic potential.
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PMID:Immunotherapy of recurrent B-cell malignancies after allo-SCT with Bi20 (FBTA05), a trifunctional anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion. 1885 12


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