Exposure to infective larvae of the filarial nematode Onchocerca volvulus (Ov) either results in patent infection (microfilaridermia) or it leads to a status called putative immunity, characterized by resistance to infection. Similar to other chronic helminth infections, there is a T cell proliferative hyporesponsiveness to Ov antigen (OvAg) by peripheral blood mononuclear cells (PBMC) from individuals with patent infection, i.e. generalized onchocerciasis (GEO), compared to PBMC from putatively immune (PI) individuals. In this study, mechanisms mediating this cellular hyporesponsiveness in GEO were investigated: the low proliferative response in PBMC from GEO individuals was associated with a lack of IL-4 production and significantly lower production of IL-5 compared to those from PI individuals, arguing against a general shift towards a T(h)2 response being the cause of hyporesponsiveness. In contrast, IL-10 and transforming growth factor (TGF)-beta, two cytokines associated with a T(h)3 response, seemed to mediate hyporesponsiveness: PBMC from individuals with GEO produced significantly more IL-10, and T cell proliferative hyporesponsiveness in this group could be reversed by the addition of anti-IL-10 and anti-TGF-beta antibodies. Hyporesponsiveness was specific for OvAg and not observed upon stimulation with related nematode antigens, arguing for a T cell-mediated, Ov-specific down-regulation. Ov-specific T cells could be cloned from GEO PBMC which have a unique cytokine profile (no IL-2 but high IL-10 and/or TGF-beta production), similar to the T cell subsets known to suppress ongoing inflammation (T(h)3 and T(r)1), indicating that this cell type which has not been found so far in infectious diseases may be involved in maintaining Ov-specific hyporesponsiveness.
One-hundred and two patients from the area of Hamburg, Germany, with vitiligo (photo-skin types II and III, Fitzpatrick classification, 1979), were examined for a possible association of the human lymphocyte antigen (HLA) complex with this disease. Antisera panels for the detection of 75 HLA antigens were utilized for this HLA typing (WHO Bulletin, 1988). The results were compared with 400 unrelated age- and sex-matched controls with photo-skin types II and III from the same geographical area. Nine of 76 vitiligo patients showed a significantly increased expression of the rare antigen HLA DRW 12 (pc = 0.000708), and 65/102 patients showed a marginally significant increased frequency of HLA A2 (pc = 0.04850) compared with controls. For HLA BW60 (40), a significant increase in frequency was shown only in the adult vitiligo group (pc = 0.0126). A ‘preventive’ antigen for the manifestation of vitiligo has not been identified in this study. A comparative analysis of all published data on the possible association of HLA with vitiligo does not support a definitive linkage to the MHC so far.
We evaluated the cytomegalovirus (CMV) serostatus as a risk factor for survival and treatment‐related mortality (TRM) in 125 patients allografted from an unrelated donor between 1994 and 1999. All patients received pretransplant in vivo T‐cell depletion using rabbit anti‐thymocyte globulin (ATG). Only one patient had primary graft failure and severe grade III/IV graft‐versus‐host disease occurred in 14% of the patients. The overall survival (OS) at 3 years was 70% for CMV‐negative patients (n = 76) and 29% in the seropositive cohort (n = 49) (P > 0·001). In multivariate analyses, CMV seropositivity remained an independent negative prognostic factor for OS (RR: 2·1; CI: 1·2–3·8; P = 0·014), apart from age > 20 years (RR: 2·74; CI: 1·2–3·8; P = 0·004) and late leucocyte engraftment (RR: 2·4; CI: 1·2–4·9; P = 0·015). The TRM for all patients was 27%. Despite monitoring for CMV antigenaemia and preemptive therapy with ganciclovir when reactivation occurred, seropositive patients had a three times higher risk of fatal treatment‐related complications than seronegative patients. In multivariate analyses, CMV seropositivity remained the strongest independent negative factor for TRM (RR: 5·3; CI: 1·9–14·6; P = 0·002), followed by age > 20 years (RR: 4·8; CI: 1·3–18·1; P = 0·02) and delayed leucocyte engraftment (RR: 3·6; CI: 1·2–11; P = 0·02). The TRM was identical in seropositive patients with (n = 27) or without (n = 22) CMV reactivation (44% versus 50%). We conclude that CMV seropositivity, despite preemptive ganciclovir therapy and even without reactivation, is a major negative prognostic factor for survival as well as for TRM in unrelated stem cell transplantation using pretransplant in vivo T‐cell depletion with ATG.
Summary. Haemophagocytic lymphohistiocytosis (HLH) isan autosomal recessive disease with histiocytic and lymphocytic in®ltrations in multiple organs. Cure seems possible only by allogeneic bone marrow transplantation (BMT), but matched sibling donors (MSD) are restricted and high mortality rates are associated with BMT from unrelated donors (URD). We report on 12 consecutive HLH patients with an improved outcome following URD transplants. Eight patients received BMT from URD, four from MSD. Five patients had signs of active HLH at the time of BMT. The conditioning regimen consisted of 20 mg/kg busulphan, 60 mg/kg VP-16 and 120 mg/kg cyclophosphamide and, in case of URD, 90 mg/kg antithymocyte globulin. The doses of busulphan and VP-16 were reduced during the programme to 16 mg/kg and 30 mg/kg, respectively. Using a ®vefold graft-versus-host disease (GVHD) prophylaxis, GVHD was absent or mild in 10, and moderate or severe in two patients undergoing unrelated transplants. One patient with URD experienced graft failure and was retransplanted on day 37. Major toxicities were hepatic veno-occlusive disease in ®ve, capillary leak syndrome in two, pneumonia in three, sepsis in one, severe mucositis in one and seizures in two patients. All patients are alive without HLH after a median follow-up of 24´5 months. One patient has chronic GVHD, another patient has severe retardation. Three patients show slight to moderate development delay. These results indicate that in HLH, BMT from matched unrelated donors should be performed. Incomplete resolution of disease activity need not impede a successful outcome.
To evaluate the schedule dependency of granulocyte colony-stimulating factor (G-CSF) (filgrastim) for stem cell mobilization, we conducted a randomized comparison in 50 healthy donors, with one subcutaneous daily injection of 10 microg/kg G-CSF (n = 25) compared with twice injections daily of 5 microg/kg G-CSF (n = 25). The two groups were well balanced for age, body weight and sex. G-CSF application was performed on an out-patient basis and leukapheresis was started in all donors on day 5. The most frequent side-effects of G-CSF were mild to moderate bone pain (88%), mild headache (72%), mild fatigue (48-60%) and nausea (8%) without differences between the two groups. The CD34(+) cell count in the first apheresis was 5.4 x 10(6)/kg donor weight (range 2.8-13.3) in the 2 x 5 microg/kg group compared with 4.0 x 10(6)/kg (range 0.4-8.8) in the 1 x 10 microg/kg group (P = 0.007). The target of collecting > 3.0 x 10(6) CD34(+) cells/kg donor weight with one apheresis procedure was achieved in 24/25 (96%) donors in the 2 x 5 microg/kg group and in 17/25 (68%) donors in the 1 x 10 microg/kg group. The target of collecting > 5.0 x 10(6) CD34(+) cells/kg in the first apheresis was achieved in 64% in the 2 x 5 microg/kg group, but in only 36% in the 1 x 10 microg/kg group. The progenitor cell assay for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) was higher in the 2 x 5 microg/kg group than in the 1 x 10 microg/kg group (7.0 vs. 3.5 x 10(5)/kg, P = 0.01; 6.6 vs. 5.0 x 10(5)/kg; P = 0.1). Administering G-CSF (filgrastim) at a dosage of 5 microg/kg twice daily rather than 10 microg/kg once daily is recommended; this leads to a higher CD34(+) cell yield and requires fewer apheresis procedures without increasing toxicity or cost.
Summary:One-hundred and two patients with good risk myeloid leukemia (CML first chronic phase or AML first CR) were transplanted from HLA-related donors after conditioning with (n ؍ 45) or without anti-thymocyte globulin (ATG) (n ؍ 57). One graft failure was observed in the non-ATG and none in the ATG group. The median time to leukocyte engraftment (Ͼ1 ؋ 10 9 /l) was 16 (range 12-33) in the ATG group and 17 days (range 11-29) in the non-ATG group (NS) and for platelet engraftment (Ͼ20 ؋ 10 9 /l) 24 and 19 days (P ؍ 0.002), respectively. Acute GVHD grade II-IV was observed in 47% of the non-ATG and in 20% of the ATG group (P ؍ 0.004). Grade III/IV GVHD occurred in 7% of the ATG and in 32% of the non-ATG group (P ؍ 0.002). Chronic GVHD was seen in 36% and 67% (P ؍ 0.005), respectively. After a median follow-up of 48 months (range 2-128), the 5-year estimated OS is 66% (95% KI: 51-81%) for the ATG group and 59% (95% KI: 46-72%) for the non-ATG group (NS). The 5-year estimated DFS is 64% (95% KI: 50-78%) for ATG and 55% (95% KI: 43-67%) for the non-ATG regimen (NS). The 5-year probability of relapse was 5% in the ATG and 15% in the non-ATG group (NS). ATG as part of the conditioning regimen leads to a significant reduction in GVHD without increase of relapse in patients with myeloid leukemia after stem cell transplantation from HLA-related donors. Allogeneic stem cell transplantation from HLA-identical siblings for patients suffering from acute or chronic myeloid leukemia has become a curative treatment option. Transplant-related mortality as the cause of death is approximately 30%, and most deaths are related directly or indirectly to acute or chronic graft-versus-host disease (GVHD). Allogeneic stem cell transplantation from HLAidentical siblings with an unmanipulated graft resulted in an incidence of acute GVHD of approximately 30 to 60%. 1 Several investigators have shown that removal of T cells from the graft by ex vivo T cell depletion resulted in a dramatic decrease in GVHD. However, it became rapidly apparent that T cell depletion resulted in a high incidence of graft failure and an increased risk of leukemia relapse. [2][3][4][5][6] Partial or selective depletion of different subpopulations of T cells, or T cell depletion with T cell add-back has been investigated and resulted either in enhanced graft failure or increased risk of GVHD after T cell add-back. [7][8][9] Other forms of T cell depletion including T cell depletion with monoclonal antibodies either in vivo or ex vivo have been investigated extensively, resulting in a decrease of GVHD, but a relatively high incidence of graft failure has been observed. 10,11 By adding monoclonal anti-52 antibodies to the conditioning regimen to deplete residual host T cells, the problem of graft failure has been partly overcome. 12 Another strategy of in vivo T cell depletion is the use of anti-thymocyte globulin as part of the conditioning regimen. We and others have recently shown that ATG as part of the preparative regimen in unrelated stem cell tran...
Summary.We have previously shown that allogeneic bone marrow transplantation (BMT) with cryopreserved donor marrow cells can be used without prolonging the engraftment time or interfering with the reconstitution of haemopoiesis. In this report we extend our initial observations of the first 40 patients who underwent allogeneic bone marrow transplantation from related donors with cryopreserved donor bone marrow for haematological malignancies, including the long-term follow-up data of the previously reported patients. The outcome of these patients was compared with that of 40 related BMT recipients receiving fresh donor bone marrow (historic control group). Time until engraftment of all patients receiving cryopreserved bone marrow was not different from the control group (ANC > 0 . 5 × 10 69 d), respectively). There was the same incidence of acute and chronic GvHD in patients receiving either cryopreserved bone marrow or fresh bone marrow (acute GvHD у II 61% v 60% and chronic GvHD 56% v 52%, respectively). Chimaerism studies showed no difference between the patient groups. Furthermore, the two groups did not differ in day 100 survival (82% v 72%). With a median follow-up of 520 d (range 47-1365 d) and 1289 d (range 48-1849 d), 60% of the patients receiving cryopreserved and 53% of the patients receiving fresh allogeneic donor bone marrow, respectively, are alive. We conclude that cryopreservation of allogeneic related donor bone marrow does not adversely affect engraftment, does not decrease the incidence of severe acute GvHD, and does not seem to affect the day 100 survival or long-term haemopoiesis.
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