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)

Pre-sensitization was investigated in the dog marrow transplant model with donor and recipient mismatching at the canine major histocompatibility complex (MHC). Various prophylactic immunosuppressive regimes were used and it was concluded from these regimes that sensitization to histocompatibility antigens could be abrogated by a combination of procarbazine and antithymocyte serum (ATS) together, before total body irradiation. Subsequent work in humans showed that rejection of a bone marrow graft can be successfully treated by using the procarbazine-antithymocyte clobulin regime and a second transplant. Based upon animal studies, attempts were made to prevent graft-versus-host disease in humans by the use of methotrexate following grafting. Despite matching at the MHC and the use of methotrexate some recipients developed graft-versus-host disease with a fatal outcome. Further work using ATS in the immediate pre- and post-grafting period was inconclusive. Accordingly ATS was used in animals once graft-versus-host disease became manifest with drmatic improvement in clinical status. As a result it was decided to treat all patients who developed graft-versus-host disease with antithymocyte globulin (ATG). Under ATG therpy twelve out of nineteen patients showed complete resolution, and five showed improvement. Six patients became long term survivors. Of the remaining 13, 11 died on interstitial pneumonitis, and two of fungal and bacterial infections. ATG in estblished graft-versus-host disease appears capable of modigying an otherwise fatal disease in a therpeutically beneficial manner.
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PMID:Use of antithymocyte serum in clinical and experimental marrow transplantation. 1 56

Forty-nine patients with severe aplastic anemia, 33 due to unknown cause, 11 drug or chemical related, 2 associated with hepatitis, 1 with paroxysmal nocturnal hemoglobinuria, and 2 possibly associated with Fanconi syndrome did not show recovery after 0.5-96 (median 2) mo of conventional therapy. Twenty-two were infected and 21 were refractory to random platelet transfusions at the time of admission. All were given marrow grafts from HLA-identical siblings. Forty-five were conditioned for grafting by cyclophosphamide (CY), 50 mg/kg on each of 4 successive days, and four by 1000 rad total body irradiation. All were given intermittent methotrexate therapy within the first 100 days of grafting to modify graft-versus-host disease (GVHD). Three patients died from infection too early to evaluate (days 1-8). Forty-six had marrow engraftment. Of these, 20 are surviving with good peripheral blood counts between 186 and 999 days, and 18 have returned to normal activities. Chronic GCHD is a problem in five. Twelve patients died of infection following rejection of the marrow graft. Twelve patients died with bacterial or fungal infections or interstitial pneumonia and active GVHD or soon following resolution of GVHD. Two patients died with marrow engraftment and no GVHD, one with an interstitial, and the other with a bacterial pneumonia. Thirty-six patients who had received random donor blood transfusions were randomly assigned to receive either CY or procarbazine-antithymocyte globulin-CY as conditioning regimens to test whether the incidence of graft rejection could be decreased. There was no difference in the incidence of graft rejection between the two regimens. In 13 patients with rejection, second transplants were attempted either with the original marrow donor (9 patients) or another HLA-identical sibling (4 patients). Three of these transplants were not evaluable, seven were unsuccessful and three were successful with only one of the three surviving for more than 468 days. In conclusion, the long-term survival of 41% of the patients in the present study is similar to that achieved in our first 24 patients, and confirms the importance of marrow transplantation for the treatment of severe aplastic anemia. Marrow graft rejection, GVHD, and infections continue to be the major causes of failure.
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PMID:Aplastic anemia treated by allogeneic bone marrow transplantation: a report on 49 new cases from Seattle. 1 59

Fifteen patients with acute leukemia resistant to standard chemotherapy were treated by bone marrow transplantation from HLA-matched siblings after conditioning with a new combination chemotherapy/radiation therapy regimen--SCARI. SCARI consists of 5 days of high-dose cytosine arabinoside and 6-thioguanine followed by 3 days of daunorubicin. After a rest period, cyclophosphamide and total-body irradiation are given sequentially. This regimen had acceptable morbidity. Median survival was 169 days. Overall survival and disease-free survival was 27% at over 11 months. Relapse rate was 13% of the entire group and 30% by actuarial projection. Relapses were late and initially extramedullary. Deaths from causes other than leukemia occurred early secondary to fungal infection and late secondary to interstitial pneumonia (frequently cytomegalovirus). Graft-versus-host disease and graft rejection were not causes of mortality. In these patients conditioned with SCARI, leukemic recurrences were infrequent but infectious complications were a major hazard.
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PMID:Bone marrow transplantation with intensive combination chemotherapy/radiation therapy (SCARI) in acute leukemia. 1 96

One hundred patients, 54 with acute myelogenous leukemia (AML) and 46 with acute lymphoblastic leukemia (ALL), considered to be in the end stages of their disease, after combination chemotherapy were treated by marrow transplantation. All patients were given a marrow graft from an HLA-identical sibling after receiving 1000-rad total body irradiation (TBI). One group of 43 patients was given cyclophosphamide (CY), 60 mg/kg on each of 2 days, 5 and 4 days before TBI. In a second group of 31 patients, additional chemotherapy was given before CY and TBI. In a third group of 19 patients, BCNU was given before CY and TBI. A fourth group of 7 patients received other chemotherapy regimens before TBI. Six patients died 3-17 days after marrow infusion without evidence of engraftment. Ninety-four patients were engrafted and only one patient rejected the graft. Thirteen patients are alive with a marrow graft, on no maintenance antileukemic therapy, and without recurrent leukemia 1-4 1/2 yr after transplantation. Three have chronic graft-versus-host disease (GVHD). Four patients are alive 1 1/2 - 3 1/2 yr after grafting but have had a relapse of their leukemia. Of 93 evaluable patients, 19 did not develop GVHD and 24 developed very mild GVHD. Fifty patients developed moderate to severe GVHD, and 40 of these were treated with antithymocyte globulin. Interstitial pneumonia occurred in 54 patients and was the primary cause of death in 34. Interstitial pneumonia often occurred in association with GVHD and the most common etiologic agent was cytomegalovirus. A total of 31 patients have had a relapse of leukemia. There was no definite correlation between relapse of leukemia and the presence or absence of GVHD. The relapse rate appeared to be relatively constant over the first 2 yr and was extremely low after that time. Neither survival nor leukemic relapse appeared to be influenced by the type of leukemia nor by the preparative chemotherapy regimen given before TBI. Patients in fair clinical condition at the time of transplantation showed significantly longer survival times than patients in poor condition (p = 0.001). This observation, coupled with the observation that some patients may be cured of their disease, indicates that marrow transplantation should now be undertaken earlier in the management of patients with acute leukemia who have an HLA-matched sibling marrow donor.
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PMID:One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. 1 51

Marrow transplants were carried out between unrelated donor-recipient pairs of dogs that were homozygous and identical for DLA-A, B, C, and D, i.e., mutually nonreactive in mixed leukocyte culture. Recipients were conditioned for transplantation by 1,200 R of total body irradiation and then treated with intermittent methotrexate for 102 days in order to prevent or delay graft-versus-host disease (GVHD). Of 13 dogs that received transplants, 4 are surviving with good grafts and no GVHD for more than 12 to 20 minutes. Nine died, 6 with GVHD between days 26 and 141, 1 with wasting on day 65, 1 with interstitial pneumonia on day 83, and 1 with graft rejection on day 23. In comparison, the survival of 17 DLA-identical littermates treated in the same manner was significantly better with 16 surviving without GVHD (P less than 0.01), while the survival of 54 DLA-nonidentical littermates was significantly worse with only two surviving without GVHD (P less than 0.025). These results are incompatible with the concept that solely the loci detected by mixed leukocyte culture and serotyping are responsible for GVHD. One or more additional loci appear to be involved. Knowledg e of this locus (loci) is important if marrow grafting between unrelated individuals is to be successful. However, results also indicate that an unrelated "compatible" marrow graft is more likely to succeed than a graft from an incompatible littermate.
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PMID:Marrow grafts between DLA-identical and homozygous unrelated dogs: evidence for an additional locus involved in graft-versus-host disease. 2 45

A chronic, debilitating syndrome related to graft-versus-host disease (GVHD) has been recognized in long-term survivors following allogeneic bone marrow transplantation. In six of 20 marrow graft recipients who survived for more than one year after receiving a transplant, this complication developed; they were studied to better define the syndrome. There was no association between the sex of either donor or recipient, HLA type, blood group, conditioning regimen or marrow cell dose and subsequent development of chronic GVHD. All six patients had mild to moderate manifestations of acute GVHD following prompt engraftment. Chronic GVHD was characterized in each patient by progression to scleroderma-like skin involvement with hyperkeratosis, reticular hyperpigmentation, atrophy with ulceration and fibrosis with limitation of joint movement. A sicca syndrome was prominent in five patients. Four patients had idiopathic interstitial pneumonitis. Infectious complications were frequent, and DNA viral infections were prominent. Autoimmune hemolytic anemia was present in three patients, and one patient had antinuclear antibody (ANA). A spectrum of immune abnormalities was observed including hypergammaglobulinemia, immunoglobulin M (IgM) paraprotein, elevated circulating immune complexes, plasma cell hyperplasia, lymphocytotoxic antibodies and autoantibodies to autologous or donor lymphocytes. Despite clinical similarity to collagen vascular diseases, none of these patients had anti-DNA antibodies or antibodies to smooth muscle, thyroid or extractable nuclear antigens. In one patient, a skin graft from the marrow donor remained healthy despite progressive involvement in recipient skin, whereas unrelated skin grafts were rejected. Immunosuppressive therapy and plasmapheresis have not been effective. Four patients have died (median survival 458 days from transplantation). Chronic GVHD appears to be a syndrome of disordered immune regulation features of immunodeficiency and autoimmunity.
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PMID:Chronic graft versus host disease: a syndrome of disordered immunity. 3 1

Bone marrow transplantation is an experimental approach to the treatment of patients with acute leukemia, aplastic anemia, and other neoplastic and genetic diseases. To date, long-term disease-free survival has been achieved in a small proportion of carefully selected patients with resistant acute leukemia. While results are not optimal, they are acceptable in late stage patients where there are no effective alterates. Major problems in marrow transplantation for leukemia include tumor resistance and a spectrum of immunologic complications including GVHD, immunodeficiency, and interstitial pneumonitis. Potential approaches to these problems have been suggested. Progress in any one area would have a substantial impact on improving survival and extending the applicability of marrow transplantation to patients at an earlier stage of their disease.
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PMID:Bone marrow transplantation in acute leukemia: current status and future directions. 4 7

Thirty-three of 85 patients undergoing marrow transplantation between 1969 and 1973 developed interstitial pneumonia; 23 died. The clinical syndrome consisted of tachypnea, cough, fever, rales, and hypoxemia; the radiologic findings were variable. The development of interstitial pneumonia was significantly associated with graft-versus-host disease and allogenic grafting; patients with isogenic grafts were relatively spared. The increased attack rate between 1969-71 (20%) and 1972-73 (49%) was not fully explained by improved long-term survival, by an increased proportion of allogenic transplants, or by an increased incidence of graft-versus-host disease. Intranuclear inclusions typical of cytomegalovirus were identified in 9 of 17 autopsy-confirmed cases, and patients whose marrow donors had positive cytomegalovirus antibody titers developed interstitial pneumonia more often than patients whose donor had negative titers. Interstitial pneumonia is an important cause of morbidity and mortality after human marrow transplantation. No effective treatment is presently available.
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PMID:Cytomegalovirus pneumonia after human marrow transplantation. 23 6

Fourteen patients with chronic granulocytic leukemia received bone marrow grafts from HLA identical siblings. Ten patients were in blast crisis prior to grafting, three were in an accelerated phase of their disease, and one was aplastic secondary to chemotherapy. Prior to transplant all patients were conditioned with chemotherapy including cyclophosphamide plus 1,000 rad of total body irradiation. Ten patients achieved engraftment while four died 1 to 26 days after marrow infusion without functioning grafts. Two patients received a second infusion of donor marrow because of delayed engraftment. Neither marrow cell dose nor presence of myelofibrosis correlated with successful engraftment. Three out of ten engrafted patients developed graft-versus-host disease. Interstitial pneumonia occurred in seven patients. The immediate cause of death was bacterial septicemia in six patients. All evidence of leukemia disappeared in nine out of ten evaluable patients. The median survival was 43 days. One patient had a complete remission of 16 months duration.
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PMID:Treatment of chronic granulocytic leukemia by chemotherapy, total body irradiation and allogeneic bone marrow transplantation. 36 30

Infections are an almost inevitable complication of human bone marrow transplantation and account for the majority of deaths in transplant recipients. Even prior to the initiation of the transplantation procedure, patients may present with infections complicating previously unsuccessful chemotherapy for hematological malignancy or aplastic anemia. Nevertheless, these pre-transplantation infections should not exclude the possibility of bone marrow transplantation if they can be successfully controlled with specific antimicrobial therapy and necessary adjunctive measures. The immediate post-transplantation period prior to engraftment is characterized by severe marrow aplasia that results from high-dose chemotherapy and total-body irradiation. Infections are primarily septicemias and localized processes caused by bacteria and fungi and their incidence increases as the intensity of immunosuppression is escalated. The high mortality associated with bacterial septicemia makes early, empirical antibacterial therapy mandatory. However, the reduction in mortality from bacterial infection resulting from such an aggressive approach may be offset by a higher mortality from invasive fungal infection, especially in patients with prior fungal colonization and undergoing prolonged conditioning therapy. Thus, until more specific and sensitive tests for the diagnosis of invasive fungal infection become available, empirical intravenous amphotericin should be considered in patients who are persistently febrile and deteriorate clinically in the face of appropriate antibacterial therapy. Interstitial pneumonia associated with severe GVHD is the major infectious complication after successful marrow engraftment and is the most significant barrier to long-term survival. Trimethoprim-sulfamethoxazole is effective prophylaxis against interstitial pneumonia due to Pneumocystis carinii, but one half of the patients still develop a pneumonitis either associated with CMV or of unknown etiology. Mortality from interstitial pneumonia is related to prior radiation therapy while survival is associated with a four-fold rise in CMV CF antibody titer. The latter observation supports the need to investigate passive immunization with CMV antibody as a means of preventing some interstitial pneumonias. Despite the progress made in many areas of human bone marrow transplantation, the majority of graft recipients still die of infectious complications. Thus, new approaches to the management of infections in transplant recipients are urgently needed. Better-tolerated oral nonabsorbable antibiotics, laminar-air-flow rooms, granulocyte transfusions, and chemotherapy and immunotherapy for CMV are among the prophylactic and therapeutic measures that must be critically evaluated in well-controlled, prospective studies. Continued assessment of the infectious complications of bone marrow transplantation is a critical aspect of any ongoing transplant program, not just a research goal...
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PMID:Infectious complications of human bone marrow transplantation. 36 7


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