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Biomedical subjects

D Senitzer

Publications and source records attributed to D Senitzer.

At least 19 recordsLinked to original sources
PubMed2005

Killer Ig-like receptor (KIR) compatibility plays a role in the prevalence of acute GVHD in unrelated hematopoietic cell transplants for AML.

Killer Ig-like receptor (KIR) is a major cluster of the natural killer cell receptors and may play a role in the outcome of hematopoietic cell transplants. A total of 65 AML cases transplanted with T-replete hematopoietic cells from unrelated donors were retrospectively KIR-genotyped by a multiplex PCR method of our own design. The KIR gene frequency and genotype patterns in these 130 samples were consistent with the data in the literature. Based upon overall inhibitory and activating KIR genes in both donors and patients, we developed an algorithm to calculate a compatibility score for each transplant case as plus, zero or minus. Significantly higher incidence (18/20, 90%) of acute (a) GVHD (grade II-IV) was found in the transplant cases with plus scores than that (25/45, 56%) in the cases with zero or minus scores (P < 0.01). When the scores are sorted in the opposite way, fewer cases (13/26, 50%) of aGVHD were found in the transplants with minus scores than that (30/39, 77%) in the transplants with zero or plus scores (P < 0.05). The difference of aGVHD prevalence between the plus score and minus score groups is highly significant (P < 0.01). KIR genotype compatibility calculated by this algorithm may predict aGVHD incidence and be helpful in choosing donors.

Acute Disease↗
PubMed2004

Cyclosporine and mycophenolate mofetil prophylaxis with fludarabine and melphalan conditioning for unrelated donor transplantation: a prospective study of 22 patients with hematologic malignancies.

In an attempt to decrease toxicity in high-risk patients undergoing unrelated donor hematopoietic stem cell transplantation (URD HSCT), we tested a combination of cyclosporine (CSP) and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis with the reduced-intensity conditioning regimen fludarabine/melphalan (Flu/Mel). A total of 22 adult patients with advanced myeloid (n=15) and lymphoid (n=7) malignancies were treated. All patients received Flu 25 mg/m2 for 5 days and Mel 140 mg/m2, with CSP 3 mg/kg daily and MMF 15 mg/kg three times a day. The median age was 49 years (range 18-66). Durable engraftment was seen in all but one patient with myelofibrosis. The 1-year nonrelapse mortality was 32%, 27% from GVHD. The cumulative incidence of acute GVHD grade 2-4 and 3-4 was 63 and 41%, respectively. With a median follow-up of 18 months, the disease-free survival (DFS) and overall survival (OS) are 55 and 59%, respectively. For patients with AML and MDS (n=14), the DFS and OS is 71%. For patients undergoing a second transplant (n=14), the DFS and OS is 57%. In conclusion, this regimen is associated with acceptable toxicity but high rates of GVHD in high-risk patients undergoing URD HSCT. Encouraging disease control for patients with advanced myeloid malignancies was observed.

Adolescent↗
PubMed2004

Development of a multiplex PCR-SSP method for Killer-cell immunoglobulin-like receptor genotyping.

Killer-cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells recognize groups of HLA class I alleles. Recent work suggests that KIR genotype may affect the outcome of hematopoietic stem-cell transplants and that prospective KIR typing maybe of benefit in future matching of donors and recipients. A simple and informative KIR genotyping method was developed using a multiplex polymerase chain reaction-sequence-specific primer strategy. This method contains four multiplex reactions for detecting all functional KIR genes, including some 2DS4 variants that harbor a common deletion. Primer pairs were designed to provide short amplicons (108-565 bp) that can be analyzed by agarose gel electrophoreses or by automated electrophoretic systems. This method was evaluated in a blinded survey with the NK/KIR Phase II QC Panel (a total of 16 cell lines) from the 14th International Histocompatibility Workshop (IHWS), and the results are 100% concordant with the consensus genotype. Results in further KIR genotyping of 20 reference cell lines from the 10th IHWS were consistent with previously published genotypes, matching those of one study in instances where different genotypes have been previously reported. The genotypes obtained in this study may be helpful to other labs developing KIR genotyping methods in resolving typing discrepancies and in detecting common deletion variants of 2DS4. This method can save labor and reagent costs. It provides good results from partially degraded template DNA due to short amplicons in this method. It is convenient to use in both clinical and research laboratories.

DNA↗
PubMed2003

Reduced-intensity allogeneic stem cell transplantation for patients whose prior autologous stem cell transplantation for hematologic malignancy failed.

Autologous hematopoietic stem cell transplantation (autoSCT) is an effective treatment for patients with various hematologic malignancies. Despite the significant improvement in the overall outcome, disease progression after transplantation remains the major cause of treatment failure. With longer follow-up, therapy-related myelodysplasia/acute myelogenous leukemia is becoming an important cause of treatment failure. The prognosis for these 2 groups of patients is very poor. Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative treatment for these patients. However, the outcome with conventional myeloablative alloSCT after failed autoSCT is typically poor because of high transplant-related mortality. In an attempt to reduce the treatment-related toxicity, we studied a reduced-intensity conditioning regimen followed by alloSCT for patients with progressive disease or therapy-related myelodysplasia/acute myelogenous leukemia after autoSCT. This report describes the outcomes of 28 patients with hematologic malignancies who received a reduced-intensity alloSCT after having treatment failure with a conventional autoSCT. Fourteen patients received a hematopoietic stem cell transplant from a related donor and 14 from an unrelated donor. The conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine in 4 patients and the combination of melphalan (140 mg/m(2)) and fludarabine in 24. Cyclosporine and mycophenolate mofetil were used for posttransplantation immunosuppressive therapy, as well as graft-versus-host disease (GVHD) prophylaxis, in all patients. All patients engrafted and had >90% donor chimerism on day 100 after SCT. Currently, 13 patients (46%) are alive and disease free, 7 patients (25%) developed disease progression after alloSCT, and 8 (32%) died of nonrelapse causes. Day 100 mortality and nonrelapse mortality were 25% and 21%, respectively. With a median follow-up of 24 months for surviving patients, the 2-year probabilities of overall survival, event-free survival, and relapse rates were 56.5%, 41%, and 41.9%, respectively. Six patients (21%) developed grade III to IV acute GVHD. Among 21 evaluable patients, 15 (67%) developed chronic GVHD. We conclude that (1) reduced-intensity alloSCT is feasible and has an acceptable toxicity profile in patients who have previously received autoSCT and that (2) although follow-up was short, a durable remission may be achieved in some patients who would otherwise be expected to have a poor outcome.

Adult↗
PubMed2001

Population coverage by HLA class-I restricted cytotoxic T-lymphocyte epitopes.

Vaccination using cytotoxic T-lymphocyte (CTL) epitopes has become a widely used immunization strategy, especially because their structure makes them an attractive alternative to the delivery of whole proteins as immunogens. Nonetheless, their use is limited, in particular because of their specificity, being recognized only by cognate HLA alleles. The potential for immunizing a substantial portion of an ethnically diverse population using a modest number of peptides has been aided by the identification of HLA supertypes. However, the derivation of epitopes is often guided by methods that do not guarantee cross-reactivity, so we consider the feasibility of providing vaccine coverage to a multi-ethnic population under different assumptions. In particular, two large datasets are used to estimate the number of peptides needed to provide > or =90% group-specific coverage of a multiethnic population, when specificity is assumed to be either to a single serologic or molecular type. These assumptions are evaluated utilizing a clinically important epitope repertoire derived from two human cytomegalovirus proteins, and data on the in vitro memory response elicited by these peptides is presented. In summary, our combined theoretical and empiric studies suggest that 90% coverage of some ethnic groups is attainable with 11 uniquely defined HLA-restricted CTL epitopes. The derivation of four or more additional CTL epitopes is needed to attain 90% coverage of Blacks or Asians, the minimally covered groups. Ninety percent coverage of all major ethnic groups in a multi-ethnic population appears feasible without relying on cross-reactivity, but may require two to three times more CTL epitopes than estimated for serologic data, homogenous populations, or HLA alleles grouped as supertypes.

Alleles↗
PubMed2000

Identification of a new HLA-B*78 allele in a Hispanic family.

A new B*78 variant, B*7804, was detected in three members of a Hispanic family. The novel B*78 sequence differs from B*78021 by two substitutions: T at nucleotide 527 (all other B*78s have A) and T at nucleotide 583 (all other B*78s have a C). Both nucleotide substitutions encode amino acid changes at codons 152 and 171, respectively.

Alleles↗
PubMed1994

Prolonged use of cyclosporine (CsA) produces reversible hemodynamic and absorptive alterations in the transplanted rat small intestine.

Cyclosporine (CsA)-induced alterations in organ blood flow (BF) and function have been studied in kidney and pancreatic transplants. In this study, we assessed the effect of prolonged CsA administration on graft tissue BF and absorption from transplanted rat small intestine (SI). Isogeneic SI transplantation was performed in Lewis rats. Animals were grouped based upon the following treatment schedules: no treatment for 1 week in group 1; 0.15 ml/kg/day im olive oil for 1 week in group 2; 0.15 ml/kg/day olive oil for 1 week and then 0.1 ml/kg/day for 5 weeks in group 3; 15 mg/kg/day im CsA for 1 week in group 4; and 15 mg/kg/day CsA for 1 week and then 10 mg/kg/day for 5 weeks in group 5. Group 6 was the same as group 5 but CsA was withdrawn for 1 week prior to assessment. Maltose absorption was measured to evaluate graft absorptive function. BF and its intramural distribution to mucosal and serosal/muscularis layers were determined using the radioactive microsphere technique. Perfusion pressure was measured to calculate vascular resistance (VR). One week of CsA of administration in group 4 resulted in a significant increase in mucosal VR (68.4 +/- 15.5 versus 46.9 +/- 8.7 U/g, P < 0.01) and significant decreases in mucosal BF (1.21 +/- 0.25 versus 1.80 +/- 0.38 ml/g/min, P < 0.01) and maltose absorption 30 min after loading (168.9 +/- 21.1 versus 214.4 +/- 28.4 glucose mg/dl, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Soluble interleukin-2 receptor levels in lupus nephritis.

Soluble interleukin-2 receptor (IL-2R) levels were measured and correlated prospectively with clinical, histologic and serologic findings over a 9-month period in 62 lupus patients. Initially, 39 patients had clinical nephritis and 23 patients did not have nephritis. The 62 lupus patients has significantly higher IL-2R than 15 normal controls, most of this difference attributable to patients with nephritis. During lupus nephritis flare 9 of 10 patients showed significant elevations of IL-2R while only 6 of the 10 patients showed either elevation of anti-DNA antibody or decrease in CH50. During disease remission or stable clinical activity changes in IL-2R levels paralleled changes in anti-DNA antibody and CH50. Nephritis patients with cellular proliferative histology had significantly higher IL-2R levels than those with membranous or mesangial nephropathy. IL-2R correlated strongly with histologic activity and chronicity indices, IgG and C3 deposition whereas anti-DNA antibody and CH50 levels did not. IL-2R levels did not correlate with serum creatinine suggesting that elevations of IL-2R were not simply due to decreased clearance. These observations suggest that serum IL-2R level is a useful marker of disease activity in lupus nephritis and may serve as a helpful adjunct in management of this disorder.

Adult↗
PubMed1990

Evidence that zero antigen-matched cyclosporine-treated renal transplant recipients have graft survival equal to that of matched recipients. Reevaluation of points.

The value of HLA matching in cadaver renal transplantation (CRT) continues to be debated. It has recently been suggested that increased importance be given to HLA matching for the distribution of cadaver kidneys. Such a policy would add both delay and expense to CRT, which could be justified only by significantly improved results. The results of CRT in 252 cyclosporine treated adult patients transplanted at our institution from November 1984 to April 1989 were reviewed. Kidneys were initially transplanted into crossmatch-negative recipients based on waiting time, regardless of match. From October 1987, a points system, based on United Network for Organ Sharing (UNOS) criteria has been used. Eighty-four pts. with zero antigen match with their donors were compared with 168 pts. sharing 1-6 Ag. Actuarial graft and patient survival were determined by the cumulative life table method and compared using a log rank test. Our results indicated no statistically significant difference in graft survival because of better matching or mismatching. These findings are in keeping with our previously reported long-term results for non-CsA pts. Past predictions of improved graft survival based upon better matching at our institution have not fulfilled expectations, with the exception of 6 Ag matches. In conclusion, increased emphasis on HLA matching with fewer "points" for poorer matches does not appear justifiable.

Adult↗
PubMed1989

Successful transplantation after conversion of a positive crossmatch to negative by dissociation of IgM antibody.

Preliminary crossmatching usually eliminates highly sensitized patients from consideration for renal transplantation. However, if the crossmatch is positive because of the presence of IgM antibody, this activity can be eliminated by treatment with the reducing agent Dithiothreitol (DTT). Successful transplantation may then be possible in patients whose crossmatch is positive due to the presence of IgM antibody. After treatment with DTT, the sera of 25 highly sensitized patients were measured for cytotoxicity against a selected panel of 40 cells. Those whose high %PRA could be attributed to blood transfusions or previous transplants did not change with DTT. Only two patients who had developed high panel reactivity, without a clear cause, had little reactivity remaining after DTT treatment of their sera. To select patients whose crossmatch might be rendered negative by DTT treatment, we developed a "minipanel" screening protocol. Patients whose monthly PRA cells increased greater than 30% from baseline had their serum samples treated with DTT to reduce IgM. The treated sera were tested against a panel of six cells. If there was little or no cytotoxicity, it was assumed that IgM antibody was responsible for the positive crossmatches. All subsequent cadaver donor crossmatches were done with and without DTT treated sera. Five patients (2 living-related; 3 cadaver) with current crossmatches positive before, but negative after, DTT treatment continue to have functioning kidneys 3-15 months after renal transplantation. There were no hyperacute rejections. We conclude that patients with IgM antibody can be successfully transplanted if they have a negative cross-match after reduction of IgM antibody in their serum samples. A "minipanel" helps to identify patients who will benefit from DTT treatment.

Adult↗
PubMed1988

Two distinct subsets of patients with systemic lupus erythematosus.

This study was undertaken to examine the levels and function of peripheral blood immunoregulatory T cell subpopulations in systemic lupus erythematosus (SLE). T cell subpopulations can be distinguished by the T cell differentiation antigens CD4 (recognized by the monoclonal antibodies OKT4 or Leu3) and CD8 (recognized by the monoclonal antibodies OKT8 or Leu2). All SLE patients tested had normal percentages of CD8 cells in their peripheral blood. The SLE patients, however, fell into two groups based on their CD4 cell numbers. Fifty-five percent of the SLE patients had normal levels of CD4 cells (Group A) and therefore normal CD4/CD8 cell ratios, whereas 45% of the SLE patient population had markedly depressed CD4 cell levels (Group B) and significantly low CD4/CD8 cell ratios. T cells from normal donors and SLE patients were further examined for their ability to stimulate allogeneic normal B/M phi cells to secrete IgM in the presence of pokeweed mitogen (PWM). Utilizing this assay system two forms of immunosuppression were observed: (1) that mediated by high concentrations of purified CD4 cells and (2) that mediated by CD8 cells. High concentrations of purified CD4 cells, added to a constant number of allogeneic normal B/M phi cells, suppressed PWM-stimulated IgM synthesis. Group B SLE patients, with significantly low CD4 cell numbers, had defective CD4 cell-mediated suppression which was concentration dependent. This result was confirmed in a study using identical twins discordant for SLE. In this case CD4 cells from the SLE twin did not induce immunosuppression at a high concentration of CD4 cells whereas similar concentrations of CD4 cells from the normal twin resulted in suppression. SLE patients (Group A) with normal levels of CD4 cells had normally immunosuppressive CD4 cells. Suppression mediated by CD8 cells was demonstrated by the fact that removal of CD8 cells resulted in enhanced IgM synthesis induced by the remaining CD4 cells. Although all the SLE patients in this study had normal peripheral blood levels of CD8 cells, SLE Group A patients had defective CD8 cell suppression whereas CD8 function appeared to be normal in Group B patients. These results suggest that in SLE patients with depressed CD4 cell numbers (Group B) there is a corresponding defect in CD4 cell function. We demonstrate that in SLE Group B patients, defective suppression is due to a subset of T cells that bear the CD4 antigen. The SLE patient population (Group A) with normal CD4/CD8 ratios and normally functioning CD4 cells, however, appear to have normal CD4 cell-mediated suppression but defective CD8 suppressor cell function.

Antibody Formation↗
PubMed1988

Pyoderma gangrenosum: a review.

Pyoderma gangrenosum is a poorly understood disease characterized by exacerbations and remissions of morphologically unique skin ulcers. It frequently is thought to be the cutaneous manifestation of an underlying systemic disease. In this review of pyoderma gangrenosum, the characteristics of the disease are described and a differential diagnosis is formulated. Associations with systemic diseases are made through a review of the literature. The pathophysiology of pyoderma gangrenosum and probable causes are considered, and special consideration is given to the immunologic mechanisms that may be operative in the disease. Finally the currently available therapeutic alternatives are reviewed.

Colitis, Ulcerative↗