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H J Deeg

Publications and source records attributed to H J Deeg.

At least 163 records · Page 9Linked to original sources
PubMed1994

Rescue from anti-MHC class II antibody-mediated marrow graft failure by c-kit ligand.

Dogs given 920 cGy of total body irradiation (TBI) followed by autologous marrow infusion uniformly achieve sustained hematopoietic reconstitution. We have previously shown that administration of the anti-MHC class II monoclonal antibody (MoAb) H81.98.21 (IgG2a) at 0.6 mg/kg/d immediately after transplantation results in delayed graft failure. A second noncrossblocking anti-MHC class II MoAb, B1F6, of the same isotype, at the same dose, did not interfere with sustained engraftment, suggesting that the observed effect was epitope dependent. Although higher concentrations of B1F6 were required, in the present study both MoAbs interfered with the propagation of long-term marrow cultures. When MoAb B1F6 was given in vivo at 1.2 mg/kg/d, ie, twice the dose used previously, dogs so treated also developed delayed marrow graft failure. Marrow failure with either MoAb involved myeloid, erythroid, and megakaryocytic lineages. Administration of recombinant canine c-kit ligand/stem cell factor (SCF) for 7 or 21 days posttransplant resulted in reversal of graft failure. Although the short course did induce a broad transient early peak of granulocytes, the longer course of SCF was accompanied by earlier sustained recovery than the short course. In conclusion, therefore, marrow graft failure induced by anti-MHC class II MoAb does not appear to be epitope dependent, involves all hematopoietic lineages, and is overcome by the administration of c-kit ligand.

Animals↗
PubMed1994

Effect of recombinant canine granulocyte-macrophage colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation.

Recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF) was studied in normal dogs and in dogs receiving otherwise lethal total body irradiation (TBI) without marrow transplant. Five normal dogs receiving 25 micrograms/kg of rcGM-CSF by subcutaneous (SC) injection twice daily (BID) for 14 days showed increases in peripheral blood neutrophil counts of three to five times the baseline. Platelet counts decreased during administration of rcGM-CSF to a mean nadir of 52,800. Ten dogs received 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow graft. Within 2 hours of TBI, rcGM-CSF was begun at a dose of 50 micrograms/kg SC BID for 5 doses and then continued at 25 micrograms/kg SC BID for 21 days. Only 1 of the 10 dogs receiving rcGM-CSF survived with complete and sustained recovery of hematopoiesis. One of 13 historical control dogs survived after 400 cGy with no hematopoietic growth factor or marrow infusion. Results with rcGM-CSF were compared with previous and concurrent data with G-CSF studied in the same model. Of 10 dogs receiving G-CSF, 8 survived with complete and sustained hematopoietic recovery, a significantly better survival than that seen with rcGM-CSF (P = .006). Neutrophil counts were sustained at higher levels after TBI for the first 18 days in the G-CSF group (P < .016) and the neutrophil nadirs were higher. No differences in neutrophil nadirs were noted between the rcGM-CSF and control groups. Dogs treated with rcGM-CSF experienced a more rapid decline of platelet counts than G-CSF-treated or control dogs over the first 18 days (P < .001). The nadir of the platelet count was higher in the control group than in either the G-CSF or rcGM-CSF group and no significant difference was observed between the G-CSF and rcGM-CSF groups. After otherwise lethal TBI (400 cGy) in dogs, rcGM-CSF was not effective in promoting hematopoietic recovery or improving survival.

Animals↗
PubMed1994

Retrovirus-mediated gene transduction into canine peripheral blood repopulating cells.

Genetically marked peripheral blood progenitor cells were used to investigate their contribution to long-term hematopoietic reconstitution after autologous marrow and peripheral blood cell transplantation. After autologous marrow harvest and cryopreservation, canine peripheral blood progenitor cells were mobilized in three dogs by treatment with recombinant canine stem cell factor for 8 days. Peripheral blood mononuclear cells were collected and enriched for major histocompatibility complex (MHC) class II antigen-positive cells by avidin-biotin immunoadsorption, thereby enriching for repopulating cells. Subsequently, the cells were cocultivated for 24 hours on irradiated vector-producing packaging cells (PA317/LN), followed by an 11-day incubation in a vector containing long-term marrow culture system. On the day of transplantation, the animals were irradiated with 9.2 Gy total body irradiation (TBI), and transduced peripheral blood cells and untransduced cryopreserved marrow cells were infused within 2 hours of TBI. All three dogs engrafted. Two dogs are long-term survivors showing intermittently G418-resistant marrow-derived colony-forming unit granulocyte-macrophage colonies at a median of 1% and 2%, respectively (range, 1% to 10%), for now up to 48 weeks after transplantation. Neo-specific sequences were detected by polymerase chain reaction in peripheral blood granulocytes for now up to 65 weeks and in peripheral blood lymphocytes for up to 75 weeks after transplantation. Peripheral blood samples of the dogs were free of helper virus and no side effects from the transduction were observed. One of the three dogs died from chronic canine distemper sclerosing encephalitis on day 84, whereas the other two dogs are alive at 15 and 17 months. Our data show successful retroviral transduction of canine peripheral blood repopulating cells. Long-term persistence of marked myeloid and lymphoid cells after transplantation suggests that peripheral blood contains repopulating cells that contribute to long-term hematopoietic reconstitution after otherwise lethal TBI.

Animals↗
PubMed1994

Hemopoietic stem cells: sources and applications.

Classically hemopoietic stem cells to be used for transplantation or autologous reinfusion have been harvested from the bone marrow which has remained the major source of stem cells for allogeneic transplantation. However, pluripotent stem cells also circulate in peripheral blood under physiological conditions and can be "mobilized" to appear in very large numbers in peripheral blood by treatment with cytotoxic chemotherapy, hemopoietic growth factors, or both. These cells are now being used widely for autologous stem cell support. They have the advantage of very rapid hemopoietic reconstitution, thereby shortening the posttransplant period of pancytopenia. Fetal liver cells, another classic source of stem cells, are currently used only infrequently. However, there is a growing interest in the use of umbilical cord blood which is rich in stem cells and easily accessible. Cord blood stem cells have been used successfully for pediatric transplants even across major histocompatibility barriers. Technology has been developed which may permit sufficient in vitro expansion so that these cells can also be used for transplants in adults. Furthermore, there is evidence that these cells may be preferable to marrow or even mobilised peripheral blood stem cells for the purpose of gene transfer.

Blood Transfusion↗
PubMed1994

Graft-versus-host disease and the development of late complications.

Graft-versus-host disease (GVHD) in both its acute and chronic forms is a severe complication after allogeneic marrow transplantation. GVHD is associated with structural and functional defects in many organs and tissues. Severe immunoincompetence may result in frequent, often severe and at times fatal infections caused by various organisms. Prolonged antibiotic prophylaxis, and possibly immunoglobulin administration are beneficial. Ocular complications, airway and pulmonary damage, and oral or dental problems may cause severe morbidity. Despite aggressive management, a proportion of patients will succumb to these complications. Severe skin disease and joint contractures are currently seen less frequently, mostly due to early treatment of the disease. Psychosocial rehabilitation of patients with chronic GVHD is a demanding and protracted challenge and should be approached by a multidisciplinary team.

Graft vs Host Disease↗
PubMed1994

Gamma-irradiation of pretransplant blood transfusions from unrelated donors prevents sensitization to minor histocompatibility antigens on dog leukocyte antigen-identical canine marrow grafts.

Pretransplant blood transfusions from a dog leukocyte antigen (DLA)-identical canine littermate marrow donor will sensitize the recipient to non-DLA-linked polymorphic minor histocompatibility antigens, which uniformly results in graft rejection. We observed previously that 2000 cGy gamma-irradiation of marrow donor blood transfusions prevented this sensitization and subsequent marrow graft rejection. The purpose of the present study was to determine whether treatment of unrelated blood transfusions with gamma-irradiation would also prevent sensitization. Conceivably, sensitization to minor histocompatibility antigens might be more efficient or potent and thus more difficult to prevent when those antigens are seen in the context of disparity for DLA antigens. Furthermore, this model, in which sensitization to DLA-identical littermate marrow is caused by unrelated blood transfusions, is directly relevant to the clinical circumstances of human marrow transplantation. We assessed sensitization caused by unrelated blood transfusions by monitoring graft outcome in recipients transplanted with DLA-identical littermate marrow after conditioning with 920 cGy total body irradiation. Two thousand cGy gamma-irradiation of unrelated blood transfusions significantly reduced the incidence of transfusion-induced sensitization of recipients. There was successful marrow engraftment in 15 of 16 (94%, P < 0.003) of these animals in contrast to the previous study in which only 7 of 16 (44%) animals engrafted after they were transfused with unmodified blood on the same schedule. These results suggest that blood transfusions for use in humans, especially for patients with aplastic anemia, should be gamma-irradiated in order to reduce the incidence of marrow graft rejection caused by sensitization to minor histocompatibility antigens.

Animals↗
PubMed1994

High-dose fractionated total-body irradiation, etoposide, and cyclophosphamide followed by autologous stem-cell support in patients with malignant lymphoma.

PURPOSE: To evaluate a high-dose treatment regimen of fractionated total-body irradiation (TBI), etoposide, and cyclophosphamide (Cy) followed by autologous stem-cell transplantation (ASCT) in patients with malignant lymphoma. PATIENTS AND METHODS: Fifty-three patients with non-Hodgkin's lymphoma (NHL; n = 43) or Hodgkin's disease (HD; n = 10) received 12.0 Gy of fractionated TBI, etoposide 60 mg/kg, and Cy 100 mg/kg followed by infusion of autologous hematopoietic stem cells. RESULTS: Thirty-one of 53 patients are alive a median of 643 (range, 177 to 1,144) days after transplant. The 2 year Kaplan-Meier (K-M) estimates of survival, event-free survival (EFS), and relapse for all 53 patients were 54%, 45%, and 43%, respectively. Sixteen of 24 patients with less advanced disease and 10 of 29 patients with more advanced disease survive free of disease for K-M estimates of EFS of 61% and 31%, respectively (P = .006). The K-M estimates of relapse were 34% for patients with less advanced disease and 53% (P = .05) for patients with more advanced disease. The K-M estimates of dying from causes other than relapse were 8% in patients with less versus 25% in patients with more advanced disease (P = .09). CONCLUSION: These data indicate that approximately 60% of patients transplanted early after failure of initial therapy for malignant lymphoma are projected to be disease-free more than 2 years after treatment with fractionated TBI, etoposide, and Cy and infusion of autologous hematopoietic stem cells. The transplant-related mortality rate is low and relapse is the main cause of treatment failure in patients with less advanced disease. For patients with more advanced disease, the K-M estimates of both transplant-related deaths (25%) and relapse (53%) remain major problems.

Adolescent↗
PubMed1994

Effect of graft-versus-host disease prophylaxis on relapse in patients transplanted for acute myeloid leukemia.

Between November 1978 and September 1988, 184 patients with acute myeloid leukemia in first remission received marrow transplants from HLA-identical siblings after conditioning with 120 mg/kg of cyclophosphamide and 12.0 Gy fractionated total body irradiation. Patients received either cyclosporine (CYA, n = 59), methotrexate (MTX, n = 82), or MTX + CYA (n = 43 as graft-versus-host disease (GVHD) prophylaxis. The probabilities of grades II-IV acute GVHD after CYA, MTX or MTX+CYA were 0.43, 0.48 and 0.28, respectively (p = 0.06). The probability of non-relapse mortality was 0.53, 0.50 and 0.42 at 4 years in patients treated with CYA, MTX, or MTX + CYA, respectively. The probability of relapse was 0.24 in patients receiving CYA, 0.24 in patients receiving MTX and 0.44 in patients receiving MTX + CYA (p = 0.02). The probability of survival at 4 years was 0.54 with CYA, 0.51 with MTX and 0.45 with MTX + CYA. A multivariate analysis of risk factors for relapse examined age, WBC at diagnosis, blast count at diagnosis, percentage of marrow blasts, FAB subtype, the number of remission induction courses to achieve a remission, maintenance therapy, consolidation therapy, marrow cell dose, donor-recipient sex, GVHD prophylaxis regimen and isolation and decontamination in laminar airflow rooms. GVHD prophylaxis with MTX + CYA was independently significantly associated with an increased risk of relapse (relative risk 2.25, p = 0.01). Acute GVHD was associated with increased non-relapse mortality (RR = 3.58, p < 0.0001). The administration of MTX + CYA did not adversely affect survival because patients receiving this regimen experienced less mortality from causes other than relapse when compared with patients receiving either CYA or MTX alone.

Adolescent↗
PubMed1994

Prophylaxis and treatment of acute graft-versus-host disease: current state, implications of new immunopharmacologic compounds and future strategies to prevent and treat acute GVHD in high-risk patients.

Acute GVHD continues to be a clinical problem, particularly after transplants from HLA-non-identical donors. Standard prophylaxis at the present time involves the use of MTX and CYA with or without the addition of glucocorticoids. The use of moAbs, in particular humanized forms such as HAT, may improve these results. A selective manipulation of cytokines (IL-1, tumor necrosis factor and others) or their receptors or both may be clinically useful. The current use of a broad variety of approaches is a clear indication that the optimum treatment has been elusive.

Acute Disease↗
PubMed1994

Secondary malignancies after marrow transplantation for leukemia or aplastic anemia.

We conclude that the most common secondary cancers which develop after marrow transplantation are lympho-proliferative disorders and solid tumors. The consequences of the secondary malignancies are serious, with more than 90% of the patients with non-Hodgkin lymphomas associated with EBV infection and more than 75% of the patients with solid tumors dying despite treatment. Secondary leukemia developing in donor T-s is rare, but was fatal in all cases. EBV infection plays a major role in leading to the non-Hodgkin lymphomas in a setting of immune dysregulation from ATG or anti-T-cell monoclonal antibody treatment of acute GVHD. Other factors are also important for development of non-Hodgkin lymphoma and include T-cell depletion of donor marrow and HLA-mismatching between donor and recipient, known to lead to dysregulation of T-lymphocyte function. These factors set up an environment of proliferative stimuli which cannot be controlled by the recovering immune system, setting the stage for a secondary cancer. The role of irradiation is becoming more prominent in association with solid tumors, particularly in aplastic anemia patients conditioned with irradiation. The final event of tumor expression is most likely the result of a cascade of events, perhaps initiated with the conditioning regimen or with stimuli to proliferation, which, after later signals, leads to malignant transformation. For lymphoproliferative disorders, the time of latency is shorter than for solid tumors, suggesting a different molecular mechanism. The incidence of oncogene expression or mutation in tumor suppressor genes in these solid tumor patients has not been investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Aplastic↗
PubMed1994

Marrow transplant experience for children with severe aplastic anemia.

PURPOSE: The two major factors associated with lack of survival after allogeneic marrow transplant for severe aplastic anemia have been graft rejection and acute graft versus host disease (GVHD). As a result, survival for patients transplanted in the 1970s was approximately 68%. Improved survival during the 1980s was primarily related to the decrease in the incidence of acute GVHD with the use of combination methotrexate and cyclosporine for GVHD prophylaxis. Although the incidence of graft rejection has not changed, the time to graft rejection has been delayed. PATIENTS AND METHODS: One hundred forty children < 18 years of age received a marrow transplant for severe aplastic anemia at the Fred Hutchinson Cancer Research Center between May, 1971 and June, 1991. Four recipients of syngeneic marrow received a simple marrow infusion, 119 recipients of HLA-identical family member marrow received cyclophosphamide (CY), 200 mg/kg; most recipients of alternative donor marrow received CY plus 12.0 Gy fractionated total body irradiation. GVHD prophylaxis was MTX only for 91 recipients of HLA-identical family member marrow, and was MTX plus CSP for all other allogeneic marrow patients. Estimates of graft rejection, acute and chronic GVHD, survival and event-free survival (EFS) were determined by the Kaplan-Meier method. RESULTS: Two recipients of syngeneic marrow achieved engraftment with donor marrow infusion only and two required immunosuppression with CY. Among the 119 recipients of HLA-identical family member marrow the type of GVHD prophylaxis did not influence graft rejection but non-transfused patients had 10% incidence of rejection compared to 22% for transfused patients (p = 0.1). All patients with late graft rejection survive whereas those with early rejection usually do not. The incidence of acute GVHD was 27% and 11% for MTX recipients and MTX plus CSP recipients, respectively (p = 0.11), and the probability of chronic GVHD was 30% and 26%, respectively. Survival is 64% for recipients of MTX and 96% for recipients of MTX plus CSP (p = 0.007), but EFS was 60% and 71%, respectively (p = 0.48). Recipients of partially matched family member or unrelated marrow donor grafts have transplants complicated by infections and GVHD. Growth and development of CY only recipients is normal and several children have been born to these former patients. CONCLUSIONS: High dose CY is usually an effective preparative regimen for children with severe aplastic anemia and an HLA-identical family member marrow donor. Additional immunosuppression with anti-thymocyte globulin may result in a further decrease in graft rejection and improved EFS. Identification of a group of children who are unlikely to respond to immunosuppressive treatment could permit earlier transplantation for patients without HLA-identical family member donors available. Children who receive CY only have normal growth and development.

Anemia, Aplastic↗
PubMed1993

Marrow toxicity of fractionated vs. single dose total body irradiation is identical in a canine model.

PURPOSE: We explored in dogs the marrow toxicity of single dose total body irradiation delivered from two opposing 60Co sources at a rate of 10 cGy/min and compared results to those seen with total body irradiation administered in 100 cGy fractions with minimum interfraction intervals of 6 hr. Dogs were not given marrow transplants. RESULTS: We found that 200 cGy single dose total body irradiation was sublethal, with 12 of 13 dogs showing hematopoietic recovery and survival. Seven of 21 dogs given 300 cGy single dose total body irradiation survived compared to 6 of 10 dogs given 300 cGy fractionated total body irradiation (p = .18). One of 28 dogs given 400 cGy single dose total body irradiation survived compared to none of six given fractionated radiation (p > .20). With granulocyte colony stimulating factor administered from day 0-21 after 400 cGy total body irradiation, most dogs survived with hematological recovery. Because of the almost uniform success with granulocyte colony stimulating factor after 400 cGy single dose total body irradiation, a study of granulocyte colony stimulating factor after 400 cGy fractionated total body irradiation was deemed not to be informative and, thus, not carried out. Additional comparisons between single dose and fractionated total body irradiation were carried out with granulocyte colony stimulating factor administered after 500 and 600 cGy of total body irradiation. As with lower doses of total body irradiation, no significant survival differences were seen between the two modes of total body irradiation, and only 3 of 26 dogs studied survived with complete hematological recovery. Overall, therefore, survival among dogs given single dose total body irradiation was not different from that of dogs given fractionated total body irradiation (p = .67). Similarly, the slopes of the postirradiation declines of granulocyte and platelet counts and the rates of their recovery in surviving dogs given equal total doses of single versus fractionated total body irradiation were indistinguishable. CONCLUSION: Within the limitations of the experimental design, we conclude that single-dose and fractionated total body irradiation have comparable marrow toxicity in dogs.

Animals↗
PubMed1993

Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia?

Optimal prophylaxis of graft-versus-host disease (GVHD) is controversial. We compared efficacy of three posttransplant immune suppressive regimens in 2,286 recipients of HLA-identical sibling bone marrow transplants for acute lymphoblastic leukemia (ALL) in first remission, acute myelogenous leukemia (AML) in first remission, or chronic myelogenous leukemia (CML) in first chronic phase. Six hundred forty received methotrexate, 977 received cyclosporine, and 669 received combined cyclosporine and methotrexate. In children, the three regimens resulted in similar outcomes. In adults, cyclosporine and methotrexate had comparable risks of acute and chronic GVHD. Compared with methotrexate, cyclosporine was associated with less interstitial pneumonia (relative risk [RR] = 0.6; P < .001), less treatment-related mortality (RR = 0.6; P < .001), more relapses (RR = 1.6; P < .05), and less treatment failure (relapse or death from any cause; RR = 0.7; P < .001). Different effects were observed in different leukemias. In ALL, the rate of leukemia relapse was increased with cyclosporine versus methotrexate, with no effect on other outcomes. In AML and CML, interstitial pneumonia, treatment-related mortality, and treatment failures were decreased with cyclosporine, with no increase in relapse. Similar analyses comparing cyclosporine plus methotrexate with cyclosporine alone showed that adults receiving the combination had less acute GVHD (RR = 0.5; P < .001), less chronic GVHD (RR = 0.7; P < .01), and less interstitial pneumonia (RR = 0.7; P < .001). Treatment failure (RR = 0.8; P < .05) was marginally reduced. Separate analyses in ALL and AML showed less acute GVHD with combined therapy, but no significant effect on other outcomes. In CML, acute GVHD, interstitial pneumonia, treatment-related mortality, and treatment failure were decreased with combined therapy.

Adolescent↗
PubMed1993

Effects of recombinant canine stem cell factor, a c-kit ligand, and recombinant granulocyte colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation.

The effects of recombinant canine stem cell factor (rcSCF) on hematopoiesis were studied in normal dogs and in dogs given otherwise lethal total body irradiation (TBI) without marrow transplant. Results were compared with previous and concurrent data with recombinant granulocyte colony-stimulating factor (rG-CSF). Four normal dogs received 200 micrograms rcSCF per kilogram body weight daily either by continuous intravenous infusion for 28 days (n = 2) or by subcutaneous (SC) injection in two divided doses for 20 days (n = 2). All dogs showed at least a twofold increase in peripheral blood neutrophil counts starting approximately 7 days after the initiation of treatment. Hematocrit level and monocyte, lymphocyte, eosinophil, reticulocyte, and platelet counts were not elevated. Marrow sections after rcSCF treatment showed panhyperplasia. The only toxicity was facial edema during the first few days of rcSCF administration, presumably caused by mast cell stimulation. Ten dogs were given 400 cGy TBI at 10 cGy/min from two opposing 60Co sources. They were given no marrow infusion and received 200 micrograms/kg/d rcSCF SC in two divided doses for 21 days starting within 2 hours of TBI. Five of the 10 dogs showed complete and sustained hematopoietic recovery and survived as compared with 1 of 28 control dogs not receiving growth factor (P < .005). RcSCF treatment allowed for hematopoietic recovery in two of seven dogs administered 500 cGy of TBI but in none of five dogs given 600 cGy of TBI. Results with rcSCF are similar to those obtained with rG-CSF. The rate of neutrophil recovery in rcSCF-treated dogs after 400 cGy TBI was not different from that of rG-CSF-treated dogs (P = .65), but the rate of platelet recovery was faster (P = .06) in the rcSCF-treated animals. Combined treatment with rcSCF and rcG-CSF after 500 cGy TBI did not result in strongly improved survival as compared with results obtained with either factor alone.

Animals↗
PubMed1993

FK-506 and methotrexate prevent graft-versus-host disease in dogs given 9.2 Gy total body irradiation and marrow grafts from unrelated dog leukocyte antigen-nonidentical donors.

FK-506 was evaluated either alone or combined with methotrexate (MTX) for prevention of graft-versus-host disease (GVHD) in dogs given 9.2 Gy total body irradiation and dog leukocyte antigen-nonidentical unrelated marrow grafts. Studies with marrow autografts showed gut toxicity and weight loss to be major side effects of FK-506. There was no hematopoietic toxicity with FK-506. In an initial allograft study, 5 dogs were given FK-506 intramuscularly at 0.3 mg/kg/day from days 0 to 8 and then orally at 0.5 mg/kg/day. All 5 died, 3 with intussusception most likely due to FK-506 toxicity, 1 with graft failure, and 1 with GVHD. Subsequently, the FK-506 dose was reduced and these drug schedules were used: FK-506 days 0-8 at 0.15 mg/kg/day i.m. and then orally at 0.5 mg/kg/day until day 90, with or without MTX intravenously at 0.4 mg/kg days 1, 3, 6, and 11. Twenty allografts were done, 10 with FK-506 alone, and 10 with MTX/FK-506. Results were compared with those in concurrent and historical controls given either no immunosuppression (n = 64), MTX (n = 114), CsA (n = 15), or MTX/CsA (n = 17). Five of 20 current dogs died with intussusception, too early to be evaluated for GVHD. The 10 dogs given FK-506 alone survived significantly better than those not given immunosuppression but not differently from those given short-term MTX or CsA alone. Three died from toxicity, 2 with graft failure, and 4 with GVHD. Only 1 dog became a long-term survivor, and this dog inadvertently received a single dose of MTX on day 7. Two of 10 dogs given MTX/FK-506 died from toxicity, 1 died with graft failure, 2 died with GVHD, and 5 became long-term survivors, a result that is significantly better than seen with either drug alone and similar to that seen with MTX/CsA. Four of the 5 survivors had no clinical GVHD. FK-506 blood levels were 15-35 ng/ml between days 8 and 15, when gut toxicity was most severe. Thereafter, levels were approximately 5 ng/ml. In conclusion, FK-506 prolonged survival of recipients of dog leukocyte antigen-nonidentical unrelated marrow grafts. When FK-506 was combined with MTX, graft-host tolerance was induced in 50% of dogs, even though FK-506 was stopped on day 90.

Animals↗
PubMed1993

Long-term survival and cure after marrow transplantation for congenital hypoplastic anaemia (Diamond-Blackfan syndrome).

Four patients with Diamond-Blackfan syndrome (congenital hypoplastic anaemia) whose disease was resistant to corticosteroid treatment and who were red blood cell transfusion-dependent, were given marrow grafts from allogeneic human-leucocyte-antigen (HLA)-identical siblings. The patients were conditioned with regimens including cyclophosphamide and busulfan. Three of four patients had sustained and complete marrow engraftment. One patient showed early signs of haematopoietic recovery but died on day 35 of pulmonary toxicity. The three surviving patients are well with normal haematopoiesis and Karnofsky performance scores of 100%, 3.0, 7.4 and 10.6 years after transplantation. Congenital hypoplastic anaemia can be treated successfully by allogeneic marrow grafts.

Acute Disease↗
PubMed1993

Inhibition of canine NK activity by anti-CD18 monoclonal antibody, UV irradiation and cyclosporine.

Previous studies from our laboratory have shown that large granular lymphocytes (LGL) mediate natural killer cell (NK) activity in dogs and that host LGL are associated with graft failure in a canine model of histoincompatible marrow transplantation. We now report studies on the effects of anti-CD18 monoclonal antibody (MAB) 60.3, ultraviolet (UV) irradiation and cyclosporine (CSP) on in vitro canine NK function. Treatment with the murine anti-CD18 MAB 60.3 produced marked diminution in lytic function (mean 79% inhibition). UV irradiation at doses greater than 1.6 millijoules/cm2 completely eliminated NK function; this effect was not due to defective effector/target conjugate formation. CSP also inhibited NK function, although in vitro lytic activity was not completely blocked (mean of 44% inhibition) at concentrations which correspond to those achieved in vivo (400 ng/mL). These observations form a basis for future investigations aimed at preventing graft failure in the canine model of histoincompatible marrow transplantation by blocking NK function in vivo.

Animals↗