6551 Background: Allogeneic transplantation has been utilized as adoptive immunotherapy for patie... more 6551 Background: Allogeneic transplantation has been utilized as adoptive immunotherapy for patients with solid tumors resistant to conventional therapy. Methods: In 2001 we started a pilot study of allogeneic hematopoietic cell transplantation after a reduced-intensity regimen in patients with metastatic, androgen-independent prostate cancer, aged 18–70, ECOG PS 0–1. Planned sample size was 10 patients. Primary endpoint was feasibility of the procedure. The conditioning regimen included thiotepa, fludarabine, and cyclophosphamide. Patients received allogeneic peripheral blood cells from an HLA-identical sibling. A median of 6.9×10e6 CD34+ cells/kg were infused (range 4.8–11.8). Graft-versus-Host Disease (GvHD) prophylaxis consisted of cyclosporine A and short-course methotrexate. All the patients were evaluable for engraftment and chimerism. Results: Six patients have been enrolled. The median age was 61 years (range 51–66). The median time to reach an absolute neutrophil count of ...
6666 Background: An immune-mediated graft-versus-tumor (GVT) effect has been reported to occur in... more 6666 Background: An immune-mediated graft-versus-tumor (GVT) effect has been reported to occur in patients with metastatic renal carcinoma receiving allogeneic transplantation. However, the onset of GVT effect is typically delayed by months from the time of the transplant, and usually follows cyclosporine withdrawal. Indeed, most patients show a tumor progression soon after the transplant, and it is questionable if patients with rapidly progressive tumor should be included in allografting protocols. METHODS We identified poor prognosis patients as those with four or more out of ten analysed prognostic factors. Prognostic factors examined were: ECOG PS; time interval from diagnosis to occurence of metastases; number of metastatic sites; liver metastases; mediastinal metastases; Hb; CRP; LDH; neutrophils; and calcium. We report the data on 53 patients with clear-cell renal carcinoma transplanted in Europe with various fludarabine-based, reduced-intensity conditioning regimens. Survival was measured from transplant date to death or last follow-up. RESULTS Median survival for poor-prognosis patients was 140 days, vs 820 days for good-prognosis patients. CONCLUSIONS Identification of prognostic subgroups can assist in result evaluation and clinical decision making about allografting in renal cell carcinoma. [Figure: see text] [Table: see text].
Bone marrow transplantation from unrelated donors is increasingly used to treat haematologicat ma... more Bone marrow transplantation from unrelated donors is increasingly used to treat haematologicat malignancies. There are almost 4 million volunteer donors now available. Therefore, it is possible to find an HLA-A, -B and -DR-identical donor for around 70% of the patients. The major obstacles to unrelated bone marrow transplantations have been rejection, severe acute graft-versus-host disease (GVHD) and prolonged immune recovery leading to frequent infections and a high transplant-related mortality. However, with improved tissue typing using DNA techniques, immunosuppression using T-cell depletion in vitro or in vivo, the frequency of acute GVHD is acceptable and the results approach those obtained with HLA-identical siblings. For patients with chronic myeloid leukaemia, the worldwide 3-year survival is around 40%. Other indications for bone marrow transplantation with unrelated marrow include acute leukaemia and myelodysplastic syndromes with high-risk features. Unrelated cord blood cells and unrelated peripheral blood progenitor cells will be increasingly used as alternative haematopoietic stem cell sources to bone marrow. Improved immunosuppression, more accurate tissue typing, growth factors and better management of infections is expected to improve outcome using unrelated haematopoietic stem ceils for transplantation in the near future.
Cytomegalovirus {CMV) has been shown to exert suppressive effects on the immune response but also... more Cytomegalovirus {CMV) has been shown to exert suppressive effects on the immune response but also to have mitogenie properties. A bacterial product, protein A from Staphylococcus aureus (SpA) was chosen to study possible inleraclions in vitro between bacterial products and adherent cells incubated with infectious CMV and ultraviolet light (UV)-inactivated CMV. Small amounts of infetiious CMV potenliated SpA-induced DNA synthesis and Ig secretion measured by induction of plaque-forming cells (PFC), The reason for this may be thai CMV in small amoums may act in synergism with the non-specilic mitogen SpA. UV-inactivated CMV did nol influence these responses except for a markedly enhanced PFC induction with SpA in lymphoeytes from seronegative individuals. This remarkable synergism with SpA was also seen in enriehed B eells. No synergism was seen in lymphocytes from seropositive donors. Large amounts of infectious CMV markedly reduced SpA-indueed immune responses. Preliminary data suggest that the immunosuppressive effects are mediated by an interleukin I inhibitory faetor. CMV was not shown to be a polyclonal B-eell activator but may, possibly in small amounts, act as such together wilh bacterial products, which would explain eeriain autoimmune phenomena. To conclude. CMV could in interaction with a bacterial product generate both synergistie and suppressive effects on immune response.
More than 12 years ago we did an allogeneic bone-marrow transplant in a 19-year-old man with chem... more More than 12 years ago we did an allogeneic bone-marrow transplant in a 19-year-old man with chemotherapy-resistant progressive Langerhans' cell histiocytosis (LCH). 1 This procedure was considered questionable. 2 Clonal histiocytosis in LCH indicates that this disease is probably a clonal neoplastic disorder. 3 We did a transplant because Langerhans' cells are replaced by donor cells after transplantation. 4 Our patient received bone marrow from his 16-year-old HLA-identical sister. He resumed work 6 months after the transplant. 1 Since then, he has been in good health. However, in Oct, 1991, he developed squamous cell cancer under his tongue. This was resected and he was treated with interferonα, 5ϫ10 6 units daily for 3 months. Interferon was discontinued because of stomatitis. He also suffered from dryness of the mouth. A biopsy showed chronic graft-versushost disease. Now he has only mild chronic graft-versus-host disease in his mouth whenever he develops a cold. Only a few patients with multisystem LCH had undergone bone-marrow transplant by 1992. 5 Four patients had allogeneic transplant from HLA-identical siblings, one died of a relapse. Two received autografts, one died of residual disease, and one was alive. 5 It is tempting to conclude that our patient is cured of LCH, because he is alive without recurrent disease more than 12 years after treatment, although a cure cannot be definitely established.We conclude that patients who have therapy-resistant life-threatening LCH should be considered for bone-marrow transplant.
JAMA: The Journal of the American Medical Association, 1993
To determine whether age over 40 years is associated with adverse outcome after allogeneic bone m... more To determine whether age over 40 years is associated with adverse outcome after allogeneic bone marrow transplantation for leukemia. A retrospective analysis of outcome after bone marrow transplants for leukemia reported to the International Bone Marrow Transplant Registry (IBMTR) among recipients 30 through 39 years, 40 through 44 years, 45 through 49 years, and 50 years of age and older. Transplantations performed in 138 institutions worldwide and reported to the IBMTR. A total of 2180 recipients of HLA-identical sibling bone marrow transplants for leukemia, divided into four cohorts based on age: 30 through 39 years (n = 1282), 40 through 44 years (n = 527), 45 through 49 years (n = 291), and 50 years and older (n = 80). Incidence of leukemia-free survival, graft-vs-host disease, and relapse was comparable among the four age cohorts. Patients with advanced leukemia aged 45 years or older had a slightly higher risk of treatment-related mortality, and the 45- through 49-year-old cohort had a higher risk of interstitial pneumonia. These data indicate that among leukemia patients over 30 years of age at the time of allogeneic bone marrow transplantation, increasing age into the fifth decade does not adversely affect outcome after transplants from HLA-identical siblings.
Post-transplant lymphoproliferative disorder (PTLD) following allogeneic hematopioetic stem cell ... more Post-transplant lymphoproliferative disorder (PTLD) following allogeneic hematopioetic stem cell transplantation (HSCT) is a fulminant disease with high mortality. The objective of this study was to determine risk factors in PTLD following HSCT in order to identify high-risk patients for surveillance, prophylaxis and treatment. Five hundred and fifty-three HSCT patients transplanted at Karolinska University Hospital in Huddinge between 1996 and 2004 were investigated retrospectively and 14 cases of PTLD were identified. Diseased patients were evaluated concerning transplantation procedure, PTLD diagnosis, treatment and outcome. Factors significant in univariate analysis were included in logistic regression multivariate analysis. The incidence of PTLD was 2.5% and the median onset of PTLD was 78 days post-transplantation. Only two PTLD patients survived. The most common therapy was anti-B-lymphocyte antibodies. Statistical analysis showed HLA mismatch (p < 0.001), mismatch in Epstein-Barr virus (EBV) serology (p < 0.001) and splenectomy (p = 0.006) to be risk factors associated with PTLD. Indeed, among 387 patients with no risk factors only one developed PTLD (0.26%). Patients with one risk factor had a probability of developing PTLD of 8.2% and those with two risk factors, a probability of 35.7%. We propose a strategy for dealing with PTLD. Patients without risk factors need not be monitored routinely. HSCT patients with one or more risk factors should be monitored weekly by polymerase chain reaction of EBV DNA, and for patients with two or more risk factors EBV-specific cytotoxic T-lymphocytes should be held in readiness before initiating the transplantation procedure.
American Journal of Obstetrics and Gynecology, 2002
Fetuses with severe combined immunodeficiency may be treated with intrauterine transplantation of... more Fetuses with severe combined immunodeficiency may be treated with intrauterine transplantation of fetal hematopoietic stem cells. In previous reports on intrauterine transplantation with T-cell-depleted bone marrow, repeated injections have led to partial immunoreconstitution at birth, with subnormal T-cell counts and a delayed response to mitogens. A male fetus with X-linked severe combined immunodeficiency because of a stop mutation in the gene encoding the common gamma chain of cytokine receptors was transplanted in week 14 of gestation with a single injection of 7 x 10(7) cryopreserved nucleated fetal liver cells (9 x 10(8) cells per estimated kilogram fetal weight) into the fetal abdomen. At 24 and 33 weeks of gestational age, fetal blood samples were taken to detect evidence of engraftment. Fetal mixed chimerism was determined using polymerase chain reaction amplification of a variable number of tandem repeats and was verified by genomic HLA class II typing and flow cytometry. The course of pregnancy, delivery, and the first 18 months of life have been uncomplicated. At week 24 of gestation, donor HLA class II alleles were detected at a low level in the background of the recipient's fetal HLA genotype. The chimeric proportion of donor cells was about 10% at 24 weeks of gestation, increasing to 50% at 33 weeks of gestation. Whereas the T-cell fraction was still markedly reduced in week 24, it increased thereafter and was in the normal range from week 33 of gestation. In vitro response to T-cell mitogens was normal from birth. In utero transplantation of cryopreserved fetal liver cells in week 14 of gestation with a single injection led to complete T- and NK-cell reconstitution at birth. Signs of engraftment were found already in week 24 of gestation. We consider intrauterine transplantation a valuable experimental method and a useful adjunct to postnatal transplantation and gene therapy in the treatment of severe combined immunodeficiency.
Preparations of Staphylococus aureus strains Cowan 1 and Wood 46 and of lipopolysaccharide (LPS) ... more Preparations of Staphylococus aureus strains Cowan 1 and Wood 46 and of lipopolysaccharide (LPS) were found to act as polyclonal B‐cell‐activating substances for human splenic and blood lymphocytes. All three substances induced polyclonal antibody secretion in blood and spleen cell cultures, as tested against fluorescein isothiocyanate‐coupled sheep erythrocytes by a modification of the local hemolysis‐in‐gel assay. Antibodies were of IgM class, as shown by inhibition of plaque formation by anti‐IgM but not by anti‐IgG or anti‐IgA antisera. All these substances also consistently induced the formation of intracellular immunoglobulin and Increased DNA synthesis in stimulated spleen cells. In blood lymphocytes Staph. aureus Cowan 1 induced a consistent increase in DNA synthesis, whereas Staph. aureus Wood and LPS often gave low or no increase in DNA synthesis. Peak antibody formation was observed on day 3 in spleen cells and on day 6 in blood lymphocyte cultures. Stimulation into high‐...
Scandinavian journal of urology and nephrology. Supplementum, 1981
Commencing 1978, we reduced the initial dose of prednisolone to 40 mg/day against a former 120-20... more Commencing 1978, we reduced the initial dose of prednisolone to 40 mg/day against a former 120-200 mg/day for cadaver kidney recipients aged 60 years and above. The patient and graft survivals at 1 year which earlier had been 59 and 47% is 69 and 46% after the change (NS). From August 1980, we reduced the initial prednisolone dose to 30 mg/day for all recipients of cadaver kidneys. From the same time, all patients were given 5 units of leukocyte poor blood prior to the transplantation, and in addition, RATG (Stanford) was given during 2 weeks immediately following the transplantation. Preceding the reduction the patient and graft survivals at 6 months were 91 and 62% while they were 88 and 88% after the reduction (NS). The intravenous dose of methylprednisolone, which is used for the treatment of acute rejection, was reduced twice in this period, first from 6 to 3 g, and then to 1.75 g total dose. The proportion of rejections, successfully treated, had remained unchanged. Our prelim...
The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characterist... more The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characteristic course and clinical manifestations. The disease is caused by a deficiency of the enzyme glucosylceramidase (cerebroside-beta-glucosidase). Studies of genomic DNA and cDNA encoding the enzyme show a single base substitution in exon 10 in the Norrbottnian patients. The enzymic lesion causes an accumulation of glucosylceramide and glucosylsphingosine in cells of the monocyte-macrophage system, particularly in spleen, liver and bone marrow. Early splenectomy results in severe symptoms from skeleton and CNS, owing to accelerated storage of glucosylceramide in these organs. Bone marrow transplantation had a life-saving effect and seems to be the method of choice for beneficial enzyme replacement therapy.
Imniunoglobulin seeretion as evidenced by plaque-forming eells (PFC) in an indireet haemolysis-in... more Imniunoglobulin seeretion as evidenced by plaque-forming eells (PFC) in an indireet haemolysis-in-gel assay, and DNA synfhesis were indueed In human blood lymphocytes by the following preparations ol cytomegalovirus (CMV): Nucleoeapsidc Nc-CMV antigen, ttiembriine M-CMV Lintigen, crude C-CMV preparations and CMV-lncubated adherent cells. Pciik stimulaiions occurred around day fi in cullure. Ne-CMV and M-CMV only stimulated PFC and DNA synthesis in lymphoeytes froin CMV seropositive individuals. C-CMV also stimulated lymphocytes from C'MV seronegative individuals bul gave betler responses in lymphocyies Irom CMV seropositive individuals. CMV-incubatcd adherent cells oecLisionally stimulated lytuphoeytes from CMV seronegative individuals but always in CMV seropusitive blood donors. Ne-. M-, and C-CMV gave high numbers of PFC in B eells enriched by sheep erythrocyte sedimentation and in co-cultures of enrtehed T and B cells. Almost no PFC were induced in enriched T cells. DNA synthesis indueed by all the three antigenie CMV preparations increased after removal ol' adhereni eells. Strong DNA synthesis was indueed in enriched T cells compared to almost itone in enriched B eells. It is concluded that some pure CMV preparations act as antigens and more crude preparations induce polyclonal activation. Different CMV preparations may be used to diagnose CMV, to study immune reactivity against CMV and as a model for CMV infections in vitro.
The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transp... more The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transplantation outcome is controversial and may differ for allogeneic and identical twin (syngeneic) bone marrow transplants. We studied the association between cell dose and outcome in 100 unmanipulated identical twin bone marrow transplantations for leukemia, reported to the International Bone Marrow Transplant Registry between 1985 and 1994, using Cox proportional hazards regression for multivariate analyses. Cell doses ranged from 0.3 to 7.4 x 10(8) nucleated cells/kg (median, 3.0 x 10(8)cells/kg). Median follow-up was 75 months. Five-year cumulative incidences of transplant-related mortality with high (more than 3 x 10(8) cells/kg) versus low (less than or equal to 3 x 10(8) cells/kg) cell doses were 2% (95% confidence interval [CI], 0% to 8%) versus 10% (95% CI, 4% to 20%), respectively. Five-year probabilities of leukemia-free survival were 53% (95% CI, 39% to 67%) and 37% (95% CI, 23%...
Long-term survival of 182 leukemic patients after allogeneic bone marrow transplantation (BMT) wa... more Long-term survival of 182 leukemic patients after allogeneic bone marrow transplantation (BMT) was analyzed retrospectively regarding the type of graft-versus-host disease (GvHD) prophylaxis and patient age. Monotherapy with either methotrexate (MTX) (n = 59) or cyclosporin (CSA) (n = 40) was given to 79 patients less than 30 years of age and to 20 older patients. These patients were compared to those receiving a combination of MTX+CSA (n = 55) or T-cell depletion (TCD) (n = 28) (38 patients < or = 30 and 45 > 30 years of age). Patient characteristics were similar in the two pairs of groups. The median follow-up time was between 4.7 and 9.6 years in the different groups. In younger patients, the incidence of grade II-IV acute GvHD was 38% amongst those treated with MTX or CSA and 14% in the MTX+CSA/TCD group (p = 0.008). Forty percent of older patients on monotherapy developed grade II-IV acute GvHD compared to 26% of those over 30 treated with MTX+CSA/TCD (ns). As a consequen...
Significantly decreased levels of all classes Ig were found in saliva and serum of 85 patients be... more Significantly decreased levels of all classes Ig were found in saliva and serum of 85 patients before and up to 5 years after bone marrow transplantation (BMT). Salivary levels of IgG were increased before BMT in patients that died shortly after transplantation (p = 0.04). Significantly higher secretory IgA (sIgA) levels in saliva were noted in patients with malignant disorders than in those with non-malignant diseases, both before (p = 0.007) and after BMT (p = 0.011). Recipients of autologous marrow had higher levels of salivary sIgA before BMT than recipients of allogeneic bone marrow (p = 0.020). With increased BM cell dose at transplantation, lower levels of salivary IgG and albumin were found. Patients with cytomegalovirus infections after transplantation showed increased salivary IgG levels (p = 0.029). Individuals with chronic GVHD had less salivary IgM one year after BMT (median value 3.2 mg/l, p = 0.04) than those without chronic GVHD (median value 42.6 mg/l). All Ig class...
6551 Background: Allogeneic transplantation has been utilized as adoptive immunotherapy for patie... more 6551 Background: Allogeneic transplantation has been utilized as adoptive immunotherapy for patients with solid tumors resistant to conventional therapy. Methods: In 2001 we started a pilot study of allogeneic hematopoietic cell transplantation after a reduced-intensity regimen in patients with metastatic, androgen-independent prostate cancer, aged 18–70, ECOG PS 0–1. Planned sample size was 10 patients. Primary endpoint was feasibility of the procedure. The conditioning regimen included thiotepa, fludarabine, and cyclophosphamide. Patients received allogeneic peripheral blood cells from an HLA-identical sibling. A median of 6.9×10e6 CD34+ cells/kg were infused (range 4.8–11.8). Graft-versus-Host Disease (GvHD) prophylaxis consisted of cyclosporine A and short-course methotrexate. All the patients were evaluable for engraftment and chimerism. Results: Six patients have been enrolled. The median age was 61 years (range 51–66). The median time to reach an absolute neutrophil count of ...
6666 Background: An immune-mediated graft-versus-tumor (GVT) effect has been reported to occur in... more 6666 Background: An immune-mediated graft-versus-tumor (GVT) effect has been reported to occur in patients with metastatic renal carcinoma receiving allogeneic transplantation. However, the onset of GVT effect is typically delayed by months from the time of the transplant, and usually follows cyclosporine withdrawal. Indeed, most patients show a tumor progression soon after the transplant, and it is questionable if patients with rapidly progressive tumor should be included in allografting protocols. METHODS We identified poor prognosis patients as those with four or more out of ten analysed prognostic factors. Prognostic factors examined were: ECOG PS; time interval from diagnosis to occurence of metastases; number of metastatic sites; liver metastases; mediastinal metastases; Hb; CRP; LDH; neutrophils; and calcium. We report the data on 53 patients with clear-cell renal carcinoma transplanted in Europe with various fludarabine-based, reduced-intensity conditioning regimens. Survival was measured from transplant date to death or last follow-up. RESULTS Median survival for poor-prognosis patients was 140 days, vs 820 days for good-prognosis patients. CONCLUSIONS Identification of prognostic subgroups can assist in result evaluation and clinical decision making about allografting in renal cell carcinoma. [Figure: see text] [Table: see text].
Bone marrow transplantation from unrelated donors is increasingly used to treat haematologicat ma... more Bone marrow transplantation from unrelated donors is increasingly used to treat haematologicat malignancies. There are almost 4 million volunteer donors now available. Therefore, it is possible to find an HLA-A, -B and -DR-identical donor for around 70% of the patients. The major obstacles to unrelated bone marrow transplantations have been rejection, severe acute graft-versus-host disease (GVHD) and prolonged immune recovery leading to frequent infections and a high transplant-related mortality. However, with improved tissue typing using DNA techniques, immunosuppression using T-cell depletion in vitro or in vivo, the frequency of acute GVHD is acceptable and the results approach those obtained with HLA-identical siblings. For patients with chronic myeloid leukaemia, the worldwide 3-year survival is around 40%. Other indications for bone marrow transplantation with unrelated marrow include acute leukaemia and myelodysplastic syndromes with high-risk features. Unrelated cord blood cells and unrelated peripheral blood progenitor cells will be increasingly used as alternative haematopoietic stem cell sources to bone marrow. Improved immunosuppression, more accurate tissue typing, growth factors and better management of infections is expected to improve outcome using unrelated haematopoietic stem ceils for transplantation in the near future.
Cytomegalovirus {CMV) has been shown to exert suppressive effects on the immune response but also... more Cytomegalovirus {CMV) has been shown to exert suppressive effects on the immune response but also to have mitogenie properties. A bacterial product, protein A from Staphylococcus aureus (SpA) was chosen to study possible inleraclions in vitro between bacterial products and adherent cells incubated with infectious CMV and ultraviolet light (UV)-inactivated CMV. Small amounts of infetiious CMV potenliated SpA-induced DNA synthesis and Ig secretion measured by induction of plaque-forming cells (PFC), The reason for this may be thai CMV in small amoums may act in synergism with the non-specilic mitogen SpA. UV-inactivated CMV did nol influence these responses except for a markedly enhanced PFC induction with SpA in lymphoeytes from seronegative individuals. This remarkable synergism with SpA was also seen in enriehed B eells. No synergism was seen in lymphocytes from seropositive donors. Large amounts of infectious CMV markedly reduced SpA-indueed immune responses. Preliminary data suggest that the immunosuppressive effects are mediated by an interleukin I inhibitory faetor. CMV was not shown to be a polyclonal B-eell activator but may, possibly in small amounts, act as such together wilh bacterial products, which would explain eeriain autoimmune phenomena. To conclude. CMV could in interaction with a bacterial product generate both synergistie and suppressive effects on immune response.
More than 12 years ago we did an allogeneic bone-marrow transplant in a 19-year-old man with chem... more More than 12 years ago we did an allogeneic bone-marrow transplant in a 19-year-old man with chemotherapy-resistant progressive Langerhans' cell histiocytosis (LCH). 1 This procedure was considered questionable. 2 Clonal histiocytosis in LCH indicates that this disease is probably a clonal neoplastic disorder. 3 We did a transplant because Langerhans' cells are replaced by donor cells after transplantation. 4 Our patient received bone marrow from his 16-year-old HLA-identical sister. He resumed work 6 months after the transplant. 1 Since then, he has been in good health. However, in Oct, 1991, he developed squamous cell cancer under his tongue. This was resected and he was treated with interferonα, 5ϫ10 6 units daily for 3 months. Interferon was discontinued because of stomatitis. He also suffered from dryness of the mouth. A biopsy showed chronic graft-versushost disease. Now he has only mild chronic graft-versus-host disease in his mouth whenever he develops a cold. Only a few patients with multisystem LCH had undergone bone-marrow transplant by 1992. 5 Four patients had allogeneic transplant from HLA-identical siblings, one died of a relapse. Two received autografts, one died of residual disease, and one was alive. 5 It is tempting to conclude that our patient is cured of LCH, because he is alive without recurrent disease more than 12 years after treatment, although a cure cannot be definitely established.We conclude that patients who have therapy-resistant life-threatening LCH should be considered for bone-marrow transplant.
JAMA: The Journal of the American Medical Association, 1993
To determine whether age over 40 years is associated with adverse outcome after allogeneic bone m... more To determine whether age over 40 years is associated with adverse outcome after allogeneic bone marrow transplantation for leukemia. A retrospective analysis of outcome after bone marrow transplants for leukemia reported to the International Bone Marrow Transplant Registry (IBMTR) among recipients 30 through 39 years, 40 through 44 years, 45 through 49 years, and 50 years of age and older. Transplantations performed in 138 institutions worldwide and reported to the IBMTR. A total of 2180 recipients of HLA-identical sibling bone marrow transplants for leukemia, divided into four cohorts based on age: 30 through 39 years (n = 1282), 40 through 44 years (n = 527), 45 through 49 years (n = 291), and 50 years and older (n = 80). Incidence of leukemia-free survival, graft-vs-host disease, and relapse was comparable among the four age cohorts. Patients with advanced leukemia aged 45 years or older had a slightly higher risk of treatment-related mortality, and the 45- through 49-year-old cohort had a higher risk of interstitial pneumonia. These data indicate that among leukemia patients over 30 years of age at the time of allogeneic bone marrow transplantation, increasing age into the fifth decade does not adversely affect outcome after transplants from HLA-identical siblings.
Post-transplant lymphoproliferative disorder (PTLD) following allogeneic hematopioetic stem cell ... more Post-transplant lymphoproliferative disorder (PTLD) following allogeneic hematopioetic stem cell transplantation (HSCT) is a fulminant disease with high mortality. The objective of this study was to determine risk factors in PTLD following HSCT in order to identify high-risk patients for surveillance, prophylaxis and treatment. Five hundred and fifty-three HSCT patients transplanted at Karolinska University Hospital in Huddinge between 1996 and 2004 were investigated retrospectively and 14 cases of PTLD were identified. Diseased patients were evaluated concerning transplantation procedure, PTLD diagnosis, treatment and outcome. Factors significant in univariate analysis were included in logistic regression multivariate analysis. The incidence of PTLD was 2.5% and the median onset of PTLD was 78 days post-transplantation. Only two PTLD patients survived. The most common therapy was anti-B-lymphocyte antibodies. Statistical analysis showed HLA mismatch (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), mismatch in Epstein-Barr virus (EBV) serology (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and splenectomy (p = 0.006) to be risk factors associated with PTLD. Indeed, among 387 patients with no risk factors only one developed PTLD (0.26%). Patients with one risk factor had a probability of developing PTLD of 8.2% and those with two risk factors, a probability of 35.7%. We propose a strategy for dealing with PTLD. Patients without risk factors need not be monitored routinely. HSCT patients with one or more risk factors should be monitored weekly by polymerase chain reaction of EBV DNA, and for patients with two or more risk factors EBV-specific cytotoxic T-lymphocytes should be held in readiness before initiating the transplantation procedure.
American Journal of Obstetrics and Gynecology, 2002
Fetuses with severe combined immunodeficiency may be treated with intrauterine transplantation of... more Fetuses with severe combined immunodeficiency may be treated with intrauterine transplantation of fetal hematopoietic stem cells. In previous reports on intrauterine transplantation with T-cell-depleted bone marrow, repeated injections have led to partial immunoreconstitution at birth, with subnormal T-cell counts and a delayed response to mitogens. A male fetus with X-linked severe combined immunodeficiency because of a stop mutation in the gene encoding the common gamma chain of cytokine receptors was transplanted in week 14 of gestation with a single injection of 7 x 10(7) cryopreserved nucleated fetal liver cells (9 x 10(8) cells per estimated kilogram fetal weight) into the fetal abdomen. At 24 and 33 weeks of gestational age, fetal blood samples were taken to detect evidence of engraftment. Fetal mixed chimerism was determined using polymerase chain reaction amplification of a variable number of tandem repeats and was verified by genomic HLA class II typing and flow cytometry. The course of pregnancy, delivery, and the first 18 months of life have been uncomplicated. At week 24 of gestation, donor HLA class II alleles were detected at a low level in the background of the recipient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s fetal HLA genotype. The chimeric proportion of donor cells was about 10% at 24 weeks of gestation, increasing to 50% at 33 weeks of gestation. Whereas the T-cell fraction was still markedly reduced in week 24, it increased thereafter and was in the normal range from week 33 of gestation. In vitro response to T-cell mitogens was normal from birth. In utero transplantation of cryopreserved fetal liver cells in week 14 of gestation with a single injection led to complete T- and NK-cell reconstitution at birth. Signs of engraftment were found already in week 24 of gestation. We consider intrauterine transplantation a valuable experimental method and a useful adjunct to postnatal transplantation and gene therapy in the treatment of severe combined immunodeficiency.
Preparations of Staphylococus aureus strains Cowan 1 and Wood 46 and of lipopolysaccharide (LPS) ... more Preparations of Staphylococus aureus strains Cowan 1 and Wood 46 and of lipopolysaccharide (LPS) were found to act as polyclonal B‐cell‐activating substances for human splenic and blood lymphocytes. All three substances induced polyclonal antibody secretion in blood and spleen cell cultures, as tested against fluorescein isothiocyanate‐coupled sheep erythrocytes by a modification of the local hemolysis‐in‐gel assay. Antibodies were of IgM class, as shown by inhibition of plaque formation by anti‐IgM but not by anti‐IgG or anti‐IgA antisera. All these substances also consistently induced the formation of intracellular immunoglobulin and Increased DNA synthesis in stimulated spleen cells. In blood lymphocytes Staph. aureus Cowan 1 induced a consistent increase in DNA synthesis, whereas Staph. aureus Wood and LPS often gave low or no increase in DNA synthesis. Peak antibody formation was observed on day 3 in spleen cells and on day 6 in blood lymphocyte cultures. Stimulation into high‐...
Scandinavian journal of urology and nephrology. Supplementum, 1981
Commencing 1978, we reduced the initial dose of prednisolone to 40 mg/day against a former 120-20... more Commencing 1978, we reduced the initial dose of prednisolone to 40 mg/day against a former 120-200 mg/day for cadaver kidney recipients aged 60 years and above. The patient and graft survivals at 1 year which earlier had been 59 and 47% is 69 and 46% after the change (NS). From August 1980, we reduced the initial prednisolone dose to 30 mg/day for all recipients of cadaver kidneys. From the same time, all patients were given 5 units of leukocyte poor blood prior to the transplantation, and in addition, RATG (Stanford) was given during 2 weeks immediately following the transplantation. Preceding the reduction the patient and graft survivals at 6 months were 91 and 62% while they were 88 and 88% after the reduction (NS). The intravenous dose of methylprednisolone, which is used for the treatment of acute rejection, was reduced twice in this period, first from 6 to 3 g, and then to 1.75 g total dose. The proportion of rejections, successfully treated, had remained unchanged. Our prelim...
The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characterist... more The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characteristic course and clinical manifestations. The disease is caused by a deficiency of the enzyme glucosylceramidase (cerebroside-beta-glucosidase). Studies of genomic DNA and cDNA encoding the enzyme show a single base substitution in exon 10 in the Norrbottnian patients. The enzymic lesion causes an accumulation of glucosylceramide and glucosylsphingosine in cells of the monocyte-macrophage system, particularly in spleen, liver and bone marrow. Early splenectomy results in severe symptoms from skeleton and CNS, owing to accelerated storage of glucosylceramide in these organs. Bone marrow transplantation had a life-saving effect and seems to be the method of choice for beneficial enzyme replacement therapy.
Imniunoglobulin seeretion as evidenced by plaque-forming eells (PFC) in an indireet haemolysis-in... more Imniunoglobulin seeretion as evidenced by plaque-forming eells (PFC) in an indireet haemolysis-in-gel assay, and DNA synfhesis were indueed In human blood lymphocytes by the following preparations ol cytomegalovirus (CMV): Nucleoeapsidc Nc-CMV antigen, ttiembriine M-CMV Lintigen, crude C-CMV preparations and CMV-lncubated adherent cells. Pciik stimulaiions occurred around day fi in cullure. Ne-CMV and M-CMV only stimulated PFC and DNA synthesis in lymphoeytes froin CMV seropositive individuals. C-CMV also stimulated lymphocytes from C'MV seronegative individuals bul gave betler responses in lymphocyies Irom CMV seropositive individuals. CMV-incubatcd adherent cells oecLisionally stimulated lytuphoeytes from CMV seronegative individuals but always in CMV seropusitive blood donors. Ne-. M-, and C-CMV gave high numbers of PFC in B eells enriched by sheep erythrocyte sedimentation and in co-cultures of enrtehed T and B cells. Almost no PFC were induced in enriched T cells. DNA synthesis indueed by all the three antigenie CMV preparations increased after removal ol' adhereni eells. Strong DNA synthesis was indueed in enriched T cells compared to almost itone in enriched B eells. It is concluded that some pure CMV preparations act as antigens and more crude preparations induce polyclonal activation. Different CMV preparations may be used to diagnose CMV, to study immune reactivity against CMV and as a model for CMV infections in vitro.
The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transp... more The impact of cell dose (number of nucleated donor cells per kilogram recipient weight) on transplantation outcome is controversial and may differ for allogeneic and identical twin (syngeneic) bone marrow transplants. We studied the association between cell dose and outcome in 100 unmanipulated identical twin bone marrow transplantations for leukemia, reported to the International Bone Marrow Transplant Registry between 1985 and 1994, using Cox proportional hazards regression for multivariate analyses. Cell doses ranged from 0.3 to 7.4 x 10(8) nucleated cells/kg (median, 3.0 x 10(8)cells/kg). Median follow-up was 75 months. Five-year cumulative incidences of transplant-related mortality with high (more than 3 x 10(8) cells/kg) versus low (less than or equal to 3 x 10(8) cells/kg) cell doses were 2% (95% confidence interval [CI], 0% to 8%) versus 10% (95% CI, 4% to 20%), respectively. Five-year probabilities of leukemia-free survival were 53% (95% CI, 39% to 67%) and 37% (95% CI, 23%...
Long-term survival of 182 leukemic patients after allogeneic bone marrow transplantation (BMT) wa... more Long-term survival of 182 leukemic patients after allogeneic bone marrow transplantation (BMT) was analyzed retrospectively regarding the type of graft-versus-host disease (GvHD) prophylaxis and patient age. Monotherapy with either methotrexate (MTX) (n = 59) or cyclosporin (CSA) (n = 40) was given to 79 patients less than 30 years of age and to 20 older patients. These patients were compared to those receiving a combination of MTX+CSA (n = 55) or T-cell depletion (TCD) (n = 28) (38 patients < or = 30 and 45 > 30 years of age). Patient characteristics were similar in the two pairs of groups. The median follow-up time was between 4.7 and 9.6 years in the different groups. In younger patients, the incidence of grade II-IV acute GvHD was 38% amongst those treated with MTX or CSA and 14% in the MTX+CSA/TCD group (p = 0.008). Forty percent of older patients on monotherapy developed grade II-IV acute GvHD compared to 26% of those over 30 treated with MTX+CSA/TCD (ns). As a consequen...
Significantly decreased levels of all classes Ig were found in saliva and serum of 85 patients be... more Significantly decreased levels of all classes Ig were found in saliva and serum of 85 patients before and up to 5 years after bone marrow transplantation (BMT). Salivary levels of IgG were increased before BMT in patients that died shortly after transplantation (p = 0.04). Significantly higher secretory IgA (sIgA) levels in saliva were noted in patients with malignant disorders than in those with non-malignant diseases, both before (p = 0.007) and after BMT (p = 0.011). Recipients of autologous marrow had higher levels of salivary sIgA before BMT than recipients of allogeneic bone marrow (p = 0.020). With increased BM cell dose at transplantation, lower levels of salivary IgG and albumin were found. Patients with cytomegalovirus infections after transplantation showed increased salivary IgG levels (p = 0.029). Individuals with chronic GVHD had less salivary IgM one year after BMT (median value 3.2 mg/l, p = 0.04) than those without chronic GVHD (median value 42.6 mg/l). All Ig class...
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