Search PubMed⌕ Search

Biomedical subjects

Effie W Petersdorf

Publications and source records attributed to Effie W Petersdorf.

At least 19 recordsLinked to original sources
PubMed2006

Immunogenomics of unrelated hematopoietic cell transplantation.

The MHC on human chromosome 6p21 encodes the HLA genes that govern histocompatibility in transplantation. Selection of potential unrelated volunteer donors for hematopoietic cell transplantation has required an understanding of the role of HLA gene products in mediating graft-versus-host and host-versus-graft alloreactions that give rise to the 'transplantation barrier'. Recent advances in the immunogenomics of the MHC in unrelated hematopoietic cell transplantation have been made through systemic examination of the alleles and antigens of large populations of racially and ethnically diverse transplant donors and recipients. The importance of non-HLA MHC-resident genetic variation in clinical outcome is increasingly being recognized. These data show that clinical outcome following transplantation is shaped by the combined effects of many genes within the MHC and their sequence polymorphisms.

Graft vs Host Disease↗
PubMed2006

Long-range multilocus haplotype phasing of the MHC.

Haplotypes are a powerful tool for identifying the genetic basis of common complex diseases. Disease-association mapping requires molecular methods for haplotyping biallelic SNP variation and highly complex polymorphisms. We developed a method for phasing HLA-A, HLA-B, and HLA-DRB1 alleles on chromosome 6 in unrelated individuals. This method uses the highly polymorphic HLA-B locus to discriminate the two HLA haplotypes in heterozygous individuals and its ideal location 1.4 Mbp telomeric to HLA-DRB1 and 1.2 Mbp centromeric to HLA-A to capture 2-Mbp-long genomic DNA. Genomic DNA representing a single HLA-B-captured haplotype is genotyped for HLA-A and HLA-DRB1 alleles and linkage to HLA-B is established. Proof of principle was established in a large blinded study of phase-known samples. Availability of an efficient method for MHC haplotype phase determination will facilitate the mapping of causative MHC-resident genes in many human diseases and has the potential to be broadened to other polymorphic gene complexes.

Genes, MHC Class I↗
PubMed2006

An acute graft-versus-host disease activity index to predict survival after hematopoietic cell transplantation with myeloablative conditioning regimens.

Algorithms for grading acute graft-versus-host disease (GVHD) are inaccurate in assessing mortality risk. We developed a method to predict mortality by using data from 386 patients with acute GVHD. From the onset of GVHD to day 100, GVHD manifestations were scored for the skin, liver, and upper and lower gastrointestinal tract, and data were recorded for immunosuppressive treatment, performance, and fever. Logistic regression models predicting nonrelapse mortality (NRM) at day 200 were developed with data from 193 randomly selected patients and then validated in the remaining 193 patients. Clinical parameters were grouped to optimize predictive accuracy measured as the area under a receiver-operator characteristic (ROC) curve. The optimal model included the total serum bilirubin concentration, oral intake, need for treatment with prednisone, and performance score. When the overall burden of GVHD was measured by using average Acute GVHD Activity Index (aGVHDAI) scores for each patient in training and validation data sets, areas under ROC curves were 0.87 and 0.85, respectively. Contour lines were generated to reflect the predicted NRM at day 200 as a function of current aGVHDAI scores. These results demonstrate that clinical manifestations of GVHD severity can be used to accurately predict the risk of NRM in real time.

Acute Disease↗
PubMed2006

Genomic polymorphism and allogeneic hematopoietic transplantation outcome.

Polymorphisms in genes that encode antigen-presenting molecules, antigen receptors, and immune mediators are crucial determinants of the risk of complications after allogeneic hematopoietic cell transplantation (allo-HCT). Matching for HLA alleles remains the cornerstone of donor selection, and recent studies are refining our understanding and use of HLA typing in allo-HCT. High-resolution allelic HLA matching generally improves transplant outcome but may limit the donor pool and delay transplantation. Allelic mismatches may be permissible in certain circumstances without compromising outcome. There is growing interest in the role of natural killer (NK) cell-mediated immunity in allo-HCT. NK cells express an array of activating and inhibitory killer cell immunoglobulin-like receptors (KIR), and NK cell activation is negatively regulated by KIR interaction with HLA class I molecules. In haploidentical transplants, NK cell alloreactivity in the graft-versus-host direction can be predicted by the HLA class I and KIR genotypes of donor and recipient and has been associated with potent graft-versus-leukemic effects and low rates of graft-versus-host disease. KIR genotype and expression may influence transplantation outcomes in both HLA-matched and -mismatched transplants. Graft-versus-host disease and major infection remain problematic despite HLA matching, and there is mounting evidence that polymorphisms in non-HLA immune mediators and host defense genes influence the risk of these complications. The importance of non-HLA genomics in nonmyeloablative transplants is poorly understood and is under investigation. These findings suggest that tissue typing for allo-HCT is entering an exciting era in which both HLA and non-HLA genomic data may be used in a more sophisticated fashion to select donors, stratify risk, identify novel therapeutic targets, and ultimately improve outcome for allo-HCT recipients.

Animals↗
PubMed2006

Genetics of risk factors for graft-versus-host disease.

Modern understanding of the genetic basis of graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (HSCT) involves knowledge of human leukocyte antigen (HLA), killer immunoglobulin-like receptors (KIR), cytokine genes, and their interactions. Insights into the immunogenetic basis of GVHD come from long-standing clinical experience in the use of myeloablative conditioning regimens and donor bone marrow as the grafting source. Under these circumstances, donor T-cell recognition of host HLA can cause GVHD. The recent elucidation of HLA class I as ligands for natural killer (NK) cell inhibitory KIR demonstrates that GVHD is the result of a complex interplay between the innate and adaptive immune responses. The extent to which T cells and NK cells contribute to clinical GVHD is a function of the host post-conditioning environment, immunosuppressive treatments, and the content of the graft source. The contribution of donor and host genetic differences in cytokine genes in modulating risks of GVHD has recently been recognized.

Cytokines↗
PubMed2005

Human leukocyte antigen matching in unrelated donor hematopoietic cell transplantation.

Hematopoietic cell transplantation (HCT) from unrelated donors is a curative therapy for many malignant and nonmalignant blood disorders. The success of unrelated HCT is influenced by the degree of human leukocyte antigen (HLA) compatibility between the donor and patient. When donor matching for HLA alleles is feasible, overall transplant outcome is superior. The presence of donor-recipient mismatching is associated with increased risk of post-transplant complications including graft rejection, acute and chronic graft-versus-host disease (GVHD), and mortality; these risks are increased with multiple HLA mismatches. For the majority of patients who lack HLA-matched unrelated donors, current research is focused on the identification of permissible HLA mismatches. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection.

Donor Selection↗
PubMed2004

Duration of immunosuppressive treatment for chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) requires long-term immunosuppressive therapy after hematopoietic cell transplantation. We retrospectively analyzed a cohort of 751 patients with chronic GVHD to identify characteristics associated with the duration of immunosuppressive treatment. Among the 274 patients who discontinued immunosuppressive therapy after resolution of chronic GVHD before recurrent malignancy or death, the median duration of treatment was 23 months. Results of a multivariable model showed that treatment was prolonged in patients who received peripheral blood cells, in male patients with female donors, in those with graft-versus-host HLA mismatching, and in those with hyperbilirubinemia or multiple sites affected by chronic GHVD at the onset of the disease. Nonrelapse mortality was increased among patients with HLA mismatching or hyperbilirubinemia but not among those with other risk factors associated with prolonged treatment for chronic GVHD. Nonrelapse mortality was also increased in older patients and those with older donors, in patients with platelet counts less than 100 000/microL or progressive onset of chronic GVHD from acute GVHD, and in those receiving higher doses of prednisone immediately before the diagnosis of chronic GVHD. After the dose of prednisone was taken into account, progressive onset was not associated with an increased risk of nonrelapse mortality.

Adolescent↗
PubMed2004

Limits of HLA mismatching in unrelated hematopoietic cell transplantation.

HLA matching between the donor and recipient improves the success of unrelated hematopoietic cell transplantation (HCT). Matched donors are available for only a minority of patients. Further information is needed to evaluate the limits of HLA mismatching. We examined the association of mortality with HLA-A, -B, -C, -DRB1, and -DQB1 mismatching in 948 patients who received a T-replete unrelated HCT for treatment of a marrow disorder. A single HLA allele or antigen mismatch was associated with increased mortality among patients with chronic myeloid leukemia (CML) within 2 years after diagnosis compared to patients with no HLA mismatch, but not among those with more advanced malignancy. In particular, a single HLA-C mismatch conferred increased risk of mortality compared to matches. There was a suggestion for increased mortality with multiple mismatches involving HLA-DQB1 compared to multiple mismatches not involving HLA-DQB1. Donors with a single HLA allele or antigen mismatch may be used for HCT when a fully matched donor is not available for patients with diseases that do not permit time for a lengthy search. Whenever possible, HLA-C mismatches should be avoided for patients with early stage CML, and HLA-DQB1 mismatches should be avoided for patients with multiple mismatches.

Alleles↗
PubMed2004

Increasingly frequent diagnosis of acute gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation.

The reported incidence of grades II to IV acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation with HLA-identical sibling donors has increased considerably during the past 15 to 20 years at our center. The purpose of this study was to evaluate the potential reasons for this change. We reviewed organ stages and overall grades of GVHD for 2220 patients who received a first marrow or peripheral blood cell transplant from an HLA-identical sibling or an HLA-allele-matched unrelated donor with the use of a posttransplantation immunosuppressive regimen that included both methotrexate and cyclosporine between 1985 and 2001. The most striking change was an increased incidence of stage 1 gut involvement from 10% to 20% before 1992 to 50% to 60% since 1992, both with related and unrelated donors. This change increased the incidence of grade II GVHD with sibling donors, such that the overall incidence of grade II to IV GVHD is now 60% to 70%. Among patients with chronic myeloid leukemia in chronic phase, the increasingly frequent diagnosis of acute GVHD since 1992 has not been associated with decreased survival. A high diagnostic sensitivity and increased awareness that gut GVHD can occur without skin involvement account for the increased incidence of acute GVHD at our center.

Acute Disease↗
PubMed2004

Evaluation of a CD25-specific immunotoxin for prevention of graft-versus-host disease after unrelated marrow transplantation.

Donor T cells activated by recipient alloantigens cause graft-versus-host disease (GVHD) after hematopoietic cell transplantation. Activated T cells express CD25, among other components of the interleukin-2 receptor. We conducted a phase I/II study to determine whether administration of CD25-specific antibody conjugated to ricin toxin A could reduce the risk of grade III or IV GVHD after marrow transplantation from HLA-matched unrelated donors. All patients received methotrexate and cyclosporine after the transplantation. The immunotoxin was given to 36 patients for 4 consecutive days beginning approximately 36 hours after the marrow infusion was completed. Fourteen (40%) of the 35 patients who could be evaluated developed grade III or IV GVHD. In a contemporaneous population of 121 patients who received marrow from HLA-matched unrelated donors and were given methotrexate and cyclosporine without the immunotoxin, the incidence of grades III and IV GVHD was 24%. Cyclosporine blocked the induction of CD25 expression on alloactivated T cells in vitro but had no detectable effect on CD25 expression by T-regulatory cells. Taken together, these results are consistent with the hypothesis that cyclosporine protected alloactivated donor T cells from the effects of the immunotoxin, whereas the CD25+ T-regulatory cells remained susceptible, causing an unexpected exacerbation of acute GVHD.

Adult↗
PubMed2004

Hematologic responses of patients with MDS to antithymocyte globulin plus etanercept correlate with improved flow scores of marrow cells.

Myelodysplastic syndrome (MDS) comprises a spectrum of heterogeneous diseases. Most patients present with ineffective hematopoiesis. The pathophysiology involves immune-mediated effects, cytokine dysregulation, and apoptosis, among others. We treated 14 transfusion-requiring patients with MDS, 10 with refractory anemia (RA) and four with RA with excess blasts (RAEB) with a 4-day course of antithymocyte globulin (ATG) followed by intermittent etanercept for 4 months. Among 13 evaluable patients, five are red blood cell and platelet transfusion independent for intervals extending beyond 2 years, and two have normalized their peripheral blood parameters. One additional patient showed a transient rise of platelet and neutrophil counts, for an overall response rate of 46%. Responding patients showed striking improvements in marrow cell abnormalities as characterized by flow cytometry. These data show that a combination of ATG plus etanercept offers effective palliative therapy for unselected patients with MDS. Further trials incorporating these two agents are warranted.

Antilymphocyte Serum↗
PubMed2004

HLA matching in allogeneic stem cell transplantation.

PURPOSE OF REVIEW: The success of unrelated hematopoietic cell transplantation (HCT) is influenced by the degree of HLA compatibility between the donor and patient. The goal of this review is to summarize new findings in the field of immunogenetics and HCT from unrelated donors using myeloablative conditioning regimens. RECENT FINDINGS: Molecular typing methods can discriminate unique alleles encoded by HLA class I and II genes. Incompatibility of donor-recipient HLA alleles increases posttransplant complications including graft rejection, acute and chronic graft-versus-host disease, and mortality. These posttransplant risks increase with increasing numbers of HLA mismatches. The identification of permissible HLA mismatches may be aided by the use of functional assays. Nongenetic factors, including the stage of disease at the time of transplantation, may influence the effect of HLA mismatching on survival. SUMMARY: HLA alleles are functionally relevant. Unrelated HCT can be optimized by comprehensive and precise donor-recipient allele matching. For patients with high-risk diseases who lack matched donors, use of donors with a single HLA mismatch may permit early treatment before disease progression.

HLA Antigens↗
PubMed2003

Allogeneic hematopoietic stem cell transplantation for myelofibrosis.

Fifty-six patients, 10 to 66 years of age, with idiopathic myelofibrosis (IMF) or end-stage polycythemia vera or essential thrombocythemia received allogeneic hematopoietic cell transplants from related (n = 36) or unrelated (n = 20) donors. Forty-four patients were prepared with busulfan plus cyclophosphamide and 12 with total body irradiation plus chemotherapy. The source of stem cells was marrow in 33 and peripheral blood in 23 patients. All but 3 patients achieved engraftment. While 50 patients showed complete donor chimerism, 3 patients were found to be mixed chimeras at 26, 48, and 86 months after transplantation, respectively. Two patients died from relapse/progressive disease, and 18 died from other causes. There are 36 patients surviving at 0.5 to 11.6 (median, 2.8) years, for a 3-year Kaplan-Meier estimate of 58% (CI, 43%-73%). Dupriez score, cytogenetic abnormalities, and degree of marrow fibrosis were the most significant risk factors for posttransplantation mortality. Patients conditioned with a regimen of busulfan targeted to plasma levels of 800 to 900 ng/mL plus cyclophosphamide had a higher probability of survival (76% [CI, 62%-91%]) than other patients. Results with unrelated donors were comparable with those with HLA-identical sibling transplants. Thus, allogeneic hematopoietic cell transplantation offers long-term relapse-free survival for patients with myelofibrosis.

Adolescent↗
PubMed2002

Structural studies of allelic diversity of the MHC class I homolog MIC-B, a stress-inducible ligand for the activating immunoreceptor NKG2D.

MIC-A and MIC-B are distant MHC class I homologs that serve as stress-inducible Ags on epithelial and epithelially derived cells. They are ligands for the widely expressed activating immunoreceptor NKG2D. To define the structural and functional consequences of sequence differences between MIC-A and MIC-B and between alleles of MIC-A and alleles of MIC-B, we determined the crystal structure of one allele of human MIC-B. Comparisons between the two previously reported MIC-A crystal structures and the MIC-B crystal structure show that, as expected, MIC-B is very similar in structure to MIC-A and likely interacts with NKG2D in an analogous manner. The interdomain flexibility observed in the MIC-A structures, a feature unique to MIC proteins among MHC class I proteins and homologs, is also displayed by MIC-B, with an interdomain relationship intermediate between the two examples of MIC-A structures. Mapping sequence variations onto the structures of MIC-A and MIC-B reveals patterns completely distinct from those displayed by classical MHC class I proteins, with a number of substitutions falling on positions likely to affect interactions with NKG2D, but with other positions lying distant from the NKG2D binding sites or buried within the core of the proteins.

Alleles↗
PubMed2002

Herpes simplex virus type 2-specific CD8 cytotoxic T lymphocyte cross-reactivity against prevalent HLA class I alleles.

Clonally expressed T-cell receptor alphabeta heterodimers are able to bind many different major histocompatibility complex/peptide combinations. This promiscuity is thought to be required for adequate surveillance against microbial and malignancy-associated antigens. After transplantation, T cells may react with nonself structures, contributing to graft-versus-host disease, in the case of hematopoietic stem cell transplantation, or graft failure, when the host immune system is preserved. We describe 2 distinct HLA A*0201-restricted, cytotoxic CD8 T-cell responses to the prevalent chronic pathogen, herpes simplex virus type 2, that cross-react with cells bearing specific alleles of the common HLA B44 family. Transfection of human or primate renal epithelial cells with HLA class I complementary DNA confirmed these results. Given the prevalence of this viral infection and the HLA alleles involved, it is possible that this cross-reactivity may be involved in clinically significant events.

Alleles↗