Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. (1/3885)

BACKGROUND: Since 1968 it has been known that bone marrow transplantation can ameliorate severe combined immunodeficiency, but data on the long-term efficacy of this treatment are limited. We prospectively studied immunologic function in 89 consecutive infants with severe combined immunodeficiency who received hematopoietic stem-cell transplants at Duke University Medical Center between May 1982 and September 1998. METHODS: Serum immunoglobulin levels and lymphocyte phenotypes and function were assessed and genetic analyses performed according to standard methods. Bone marrow was depleted of T cells by agglutination with soybean lectin and by sheep-erythrocyte rosetting before transplantation. RESULTS: Seventy-seven of the infants received T-cell-depleted, HLA-haploidentical parental marrow, and 12 received HLA-identical marrow from a related donor; 3 of the recipients of haploidentical marrow also received placental-blood transplants from unrelated donors. Except for two patients who received placental blood, none of the recipients received chemotherapy before transplantation or prophylaxis against graft-versus-host disease. Of the 89 infants, 72 (81 percent) were still alive 3 months to 16.5 years after transplantation, including all of the 12 who received HLA-identical marrow, 60 of the 77 (78 percent) who were given haploidentical marrow, and 2 of the 3 (67 percent) who received both haploidentical marrow and placental blood. T-cell function became normal within two weeks after transplantation in the patients who received unfractionated HLA-identical marrow but usually not until three to four months after transplantation in those who received T-cell-depleted marrow. At the time of the most recent evaluation, all but 4 of the 72 survivors had normal T-cell function, and all the T cells in their blood were of donor origin. B-cell function remained abnormal in many of the recipients of haploidentical marrow. In 26 children (5 recipients of HLA-identical marrow and 21 recipients of haploidentical marrow) between 2 percent and 100 percent of B cells were of donor origin. Forty-five of the 72 children were receiving intravenous immune globulin. CONCLUSIONS: Transplantation of marrow from a related donor is a life-saving and life-sustaining treatment for patients with any type of severe combined immunodeficiency, even when there is no HLA-identical donor.  (+info)

Thymic selection by a single MHC/peptide ligand: autoreactive T cells are low-affinity cells. (2/3885)

In H2-M- mice, the presence of a single peptide, CLIP, bound to MHC class II molecules generates a diverse repertoire of CD4+ cells. In these mice, typical self-peptides are not bound to class II molecules, with the result that a very high proportion of H2-M- CD4+ cells are responsive to the various peptides displayed on normal MHC-compatible APC. We show here, however, that such "self" reactivity is controlled by low-affinity CD4+ cells. These cells give spectacularly high proliferative responses but are virtually unreactive in certain other assays, e.g., skin graft rejection; responses to MHC alloantigens, by contrast, are intense in all assays. Possible explanations for why thymic selection directed to a single peptide curtails self specificity without affecting alloreactivity are discussed.  (+info)

Risk factors for severe hemorrhagic cystitis following BMT. (3/3885)

Hemorrhagic cystitis (HC) is a common toxicity of preparative regimens for bone marrow transplantation (BMT). Severe HC often requires prolonged and expensive hospitalization, and occasionally can result in death. To investigate the risk factors for severe HC, we conducted a retrospective study among 1908 patients who received BMTs at the University of Minnesota during 1974 to 1993. A previous report from our institution reported on 977 of these patients. We identified all patients with genitourinary complication within 100 days post-BMT from the BMT database. Medical charts for these patients were reviewed to determine whether the patient had HC and also the grade of HC. A total of 208 HC cases were identified during the study period. Of them, 92 patients had severe HC, an incidence of 5% (95% CI = 4-6%). We found that grade II-IV graft-versus-host disease (RR = 2.56; 95% CI = 1.43-4.56), use of busulfan (RR = 2.69; 95% CI = 1.35-5.35), and age at transplant (RR = 2.20; 95% CI = 1.27-3.81, for age of 10-30 compared to age of 0-9) were related to an increased risk of HC. In contrast, transplant year was inversely associated with the risk of HC (trend test, P < 0.01). We did not find any significant difference in HC with the use of prophylactic Mesna.  (+info)

Nephrotic syndrome as a clinical manifestation of graft-versus-host disease (GVHD) in a marrow transplant recipient after cyclosporine withdrawal. (4/3885)

GVHD is one of the most frequent complications of BMT and recently nephrotic syndrome (NS) has been described as a manifestation of chronic GVHD. Here, we present an AA patient who developed NS 1 year after BMT when cyclosporine was stopped. Renal biopsy showed focal sclerosis associated with membranous deposits. He also had other clinical manifestations of chronic GVHD: sicca-like syndrome and colestasis. After 15 days of CsA therapy, he experienced a remarkable improvement in the NS and GVHD as a whole. We comment on immunological mechanisms that could be involved in the pathogenesis of this manifestation.  (+info)

T cell subsets in experimental lupus nephritis: modulation by bacterial superantigen. (5/3885)

Chronic graft-vs-host disease (GvH), induced by injection of DBA/2 lymphocytes into (C57BL/6 x DBA/2)F1 hybrids, is a murine model for lupus nephritis, associated with a Th2-dependent polyclonal B cell activation. The development of glomerulosclerosis in this model is preceded by a glomerular influx of LFA-1+ T cells. We investigated whether exposure to bacterial superantigen would modulate the course of this autoimmune syndrome. Injection of the bacterial superantigen staphylococcal enterotoxin B (SEB) in mice has been shown to induce the activation of TcRVbeta8+ T cells. Within 2 weeks after GvH induction, mice were injected twice with 20 microg of SEB and the following parameters were examined: cytokine and Ig profile, proteinuria and renal pathology. The second SEB injection induced in GvH mice an increased release of both interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) as compared with control F1 mice. No differences were observed in IL-2 production. SEB-treated GvH mice demonstrated a delayed onset of proteinuria. Histological analysis of the kidney showed that SEB-challenged GvH mice displayed significantly more interstitial inflammation and mesangial proliferation together with more IgG2a deposits in glomeruli than non-injected GvH mice. From these results, we conclude that GvH mice are more responsive to SEB in terms of cytokine production and that bacterial infection can modulate the course of this renal disease from a membranous to a more proliferative type of nephropathy.  (+info)

High dose chemotherapy with busulfan, cyclophosphamide, and etoposide as conditioning regimen for allogeneic bone marrow transplantation for patients with acute myeloid leukemia in first complete remission. (6/3885)

We explored the combination of busulfan/cyclophosphamide/etoposide as conditioning regimen prior to bone marrow transplantation in 31 patients with acute myeloid leukemia (AML) in first complete remission. The preparative regimen consisted of 16 mg/kg busulfan, 30-60 mg/kg VP-16, and 120 mg/kg cyclophosphamide. With a median follow-up of 30.5 months (range, 5-60 months), 25 patients are alive in continuous complete remission. Estimated disease-free survival at 5 years is 80.5%. Death was due to transplant-related toxicity (graft-versus-host disease and cytomegalovirus infection, graft-versus-host disease and pneumonia, sepsis and mucositis, respectively). None of the patients have relapsed. As demonstrated by the results of this analysis, the conditioning regimen busulfan/cyclophosphamide/etoposide is effective and well tolerated in patients with AML in first complete remission. Main nonhematological toxicities were mucositis and hepatotoxicity. The low mortality and relapse rate appears to justify allogeneic bone marrow transplantation for patients with AML in first complete remission who have an HLA-identical donor. Whether this regimen offers a substantial improvement in disease-free and overall survival over presently used regimens warrants further investigation.  (+info)

Long-term follow-up of high-risk allogeneic peripheral-blood stem-cell transplant recipients: graft-versus-host disease and transplant-related mortality. (7/3885)

PURPOSE: To determine the risks of graft-versus-host disease (GVHD) and transplant-related mortality after allogeneic peripheral-blood stem-cell (PBSC) transplantation. PATIENTS AND METHODS: Between December 1994 and July 1996, 50 consecutive patients with high-risk hematologic malignancies in first remission or relapse received high-dose therapy followed by transplantation of granulocyte colony-stimulating factor-mobilized, allogeneic PBSCs collected from HLA-identical siblings. GVHD prophylaxis included cyclosporine and corticosteroids. RESULTS: As of April 1, 1998, 18 patients (36%+/-13%) survived with a median follow-up period of 767 days (range, 602 to 1,127 days). The actuarial probability of grades 2-4 acute GVHD was 0.37+/-0.14 (95% confidence interval). Of 36 assessable patients, 26 (72%+/-15%) developed chronic GVHD. The actuarial probability of chronic GVHD 2 years after transplantation was 0.87+/-0.15. Of 14 progression-free survivors, 11 (79%+/-22%) have active, chronic GVHD. All 11 patients require ongoing immunosuppression, and nearly two thirds have extensive disease. Thirteen patients died as a result of transplant-related mortality (26%+/-12%), six (12%) before and seven (14%) after day +100. CONCLUSION: We observed a high risk of chronic GVHD after allogeneic PBSC transplantation, which compromised the performance status of most long-term survivors and resulted in a relatively high risk of late transplant-related mortality. Approximately 75% of transplant-related deaths were associated with GVHD; thus, reduction in transplant-related mortality after allogeneic PBSC transplantation will require more effective strategies for the prophylaxis and/or treatment of GVHD.  (+info)

Comparative outcomes of T-cell-depleted and non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: impact of donor lymphocyte infusion. (8/3885)

PURPOSE: Donor lymphocyte infusion (DLI) can restore complete remission in patients with chronic myelogenous leukemia (CML) who have relapsed after T-cell-depleted (TCD) allogeneic bone marrow transplantation (BMT). The existence of salvage treatment for patients with DLI after TCD allogeneic BMT prompted an evaluation of overall outcome after CD6+ -TCD allogeneic BMT for patients treated during the time when DLI has been available. PATIENTS AND METHODS: We performed a retrospective analysis of outcomes of 46 patients who underwent TCD allogeneic BMT for stable-phase CML and compared these outcomes with those of 40 patients who underwent non-TCD allogeneic BMT. All subjects were patients at one of two neighboring institutions during a period when DLI was available. All patients received marrow from HLA-identical sibling donors, underwent similar myeloablative regimens, and had similar pretreatment characteristics. RESULTS: After BMT, the TCD group had a lower incidence of grade 2 to 4 acute (15% v 37%, P = .026) and chronic graft-versus-host disease (GVHD) (18% v 42%, P = .024) than did the non-TCD group. The 1-year treatment-related mortality rates for the TCD group and the non-TCD group were 13% and 29%, respectively (P = .07). The estimated 3-year probability of relapse (cytogenetic or hematologic) was higher for patients in the TCD group than for patients in the non-TCD group (62% v 24%, P = .0003). Twenty-three patients (20 in the TCD group and three in the non-TCD group) received and were assessable for response to DLI. After DLI, 17 of 20 patients in the TCD group and two of three patients in the non-TCD group achieved complete remission. Donor lymphocyte infusion induced GVHD in nine of 23 patients. Thirty (65%) of 46 patients in the TCD group and 27 (69%) of 39 assessable patients in the non-TCD group remained alive without evidence of disease. The estimated 3-year overall survival rates were similar for the TCD group and the non-TCD group (72% v 68%, respectively; P = .38). At last follow-up, there was no difference in the overall prevalence of GVHD or the proportion of patients requiring immunosuppressive agents between groups. CONCLUSION: These results suggest that the combination of T-cell depletion and post-BMT DLI is a viable treatment option for patients undergoing allogeneic BMT for CML and should be prospectively compared with traditional forms of GVHD prophylaxis.  (+info)