Human leukocyte antigens antibodies after lung transplantation: Primary results of the HALT study.

Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA. The median DSA mean fluorescence intensity (MFI) was 3197. We identified a significant association between the Lung Allocation Score and the development of DSA (HR = 1.02, 95% CI: 1.001-1.03, P = .047) and a significant association between DSA with an MFI ≥ 3000 and acute cellular rejection (ACR) grade ≥ A2 (HR = 2.11, 95% CI: 1.04-4.27, P = .039). However, we did not detect an association between DSA and survival. We conclude that DSA occur frequently early after lung transplantation, and most target class II HLA. DSA with an MFI ≥ 3000 have a significant association with ACR. Extended follow-up is necessary to determine the impact of DSA on other important outcomes.

Concordance and discordance in anti-HLA antibody testing.

BACKGROUND: Correct identification of the specificity of antibodies directed against HLA using single antigen Luminex beads (SALB) is essential in current HLA laboratory practice for transplantation. The aim of this study was to investigate the magnitude of concordance and discordance among laboratories in testing for anti-HLA antibodies using SALB. METHOD: 35 sera were distributed by the ASHI Proficiency Testing Program to HLA laboratories worldwide. We analyzed 4335 test results submitted between April 2010 and April 2013 by participating laboratories. RESULTS: SALB was used by approximately 94% of the participating laboratories, yet concordant assignment of antibody specificity was imperfect. For each serum, the assignment of an average of 10 antibody specificities was discordant. Disagreement was observed for antibodies directed against common as well as uncommon antigens. The assignment of an average of 15 antibody specificities in each "positive" serum appeared to be influenced by vendor-dependent causes. Inter-vendor concordance was lower than intra-vendor concordance, indicating that vendor dependent factors may be a central cause for disagreement. CONCLUSIONS: Our study illustrates the prevalence of concordance and discordance, also affected by unpremeditated causes, in reporting SALB antibody results. Insufficient concordance and standardization in antibody testing may have practical implications for organ allocation and organ sharing programs.

Birth order and transplantation outcome in HLA-identical sibling stem cell transplantation: an analysis on behalf of the Center for International Blood and Marrow Transplantation.

Allogeneic stem cell transplantation (SCT) is the most effective treatment option for many hematologic malignancies, but graft-versus-host disease (GVHD) remains a major cause of treatment failure. Along with well-established risk factors for transplantation outcomes, recent single-center studies have identified a birth order effect in HLA-identical sibling SCT, with lower rates of acute and chronic GVHD and improved overall survival when the donor is younger than the recipient. One hypothesized mechanism for this effect is microchimerism due to fetomaternal and transmaternal sibling cell trafficking during pregnancy as the donor is exposed to recipient antigens in utero. The aim of the present study was to validate previously reported single-center data in a large, multicenter cohort provided by the Center for International Blood and Marrow Transplantation. All adult and pediatric patients (n = 11,365) with a hematologic malignancy who underwent allogeneic SCT with a graft from an HLA-identical sibling donor between 1990 and 2007 were included. When donors were younger than recipients, there was a significantly lower rate of acute GVHD grade II-IV and chronic GVHD in children, as well as a lower rate of chronic GVHD in adolescents. However, the hypothesized overall positive effect of lower relapse and better survival when donors are younger than recipients was not observed. Our data suggest that if otherwise equally matched, a graft from a younger sibling may be superior to a graft from an older sibling for children and adolescents undergoing SCT.

Progression of morphological changes after transplantation of a liver with heterozygous α-1 antitrypsin deficiency.

Inadvertent transplantation of an α-1 antitrypsin-deficient liver into an adult man provided a unique opportunity to follow the natural history of morphological changes in serial liver biopsies. After doing well initially, the patient developed liver function test abnormalities 6 years posttransplant, but biopsies at that time and 2 years later revealed only chronic hepatitis with no specific features. It was only upon repeat biopsy 10 years posttransplant that characteristic cytoplasmic inclusions appeared. Genotypic and phenotypic testing of pretransplant and posttransplant specimens confirmed α-1 antitrypsin deficiency in the transplanted liver. Serologic tests for viral hepatitis and autoimmune disease were negative throughout the pretransplant and posttransplant period. The case suggests that patients with chronic hepatitis of unknown etiology should be tested for the possibility of α-1 antitrypsin deficiency and illustrates the prolonged course that may precede the development of typical cytoplasmic inclusions in the liver.

Allogeneic hematopoietic cell transplantation in human immunodeficiency virus-positive patients with hematologic disorders: a report from the center for international blood and marrow transplant research.

The role of allogeneic hematopoietic cell transplantation (alloHCT) in human immunodeficiency virus (HIV)-positive patients is not known. Using the Center for International Blood and Marrow Transplant Research database, we retrospectively evaluated 23 HIV-positive patients undergoing matched sibling donor (n = 19) or unrelated donor (n = 4) alloHCT between 1987 and 2003. The median age at alloHCT was 32 years. Indications for alloHCT were diverse and included malignant (n = 21) and nonmalignant (n = 2) hematologic disorders. Nine patients (39%) underwent transplantation after 1996, the approximate year that highly active antiretroviral therapy became standard treatment. The median time to neutrophil engraftment was 16 days (range, 7 to 30 days), and the cumulative incidences of grade II-IV acute graft-versus-host disease (aGVHD) at 100 days, chronic GVHD (cGVHD), and survival at 2 years were 30% (95% confidence interval [CI] = 14% to 50%), 28% (95% CI = 12% to 48%), and 30% (95% CI = 14% to 50%), respectively. At a median follow-up of 59 months, 6 patients were alive. Survival appears to be better in the patients undergoing alloHCT after 1996; 4 of these 9 patients survived, compared with only 2 of 14 those undergoing transplantation before 1996. These data suggest that alloHCT is feasible for selected HIV-positive patients with malignant and nonmalignant disorders. Prospective studies are needed to evaluate the safety and efficacy of this modality in specific diseases in these patients.

A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer.

PURPOSE: Patients with advanced cancer received temsirolimus (Torisel, CCI-779), a novel inhibitor of mammalian target of rapamycin, i.v. once daily for 5 days every 2 weeks to determine the maximum tolerated dose, toxicity profile, pharmacokinetics, and preliminary antitumor efficacy. EXPERIMENTAL DESIGN: Doses were escalated in successive cohorts of patients using a conventional phase I clinical trial design. Samples of whole blood and plasma were collected to determine the pharmacokinetics of temsirolimus and sirolimus, its principal metabolite. RESULTS: Sixty-three patients were treated with temsirolimus (0.75-24 mg/m(2)/d). The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum tolerated dose was 15 mg/m(2)/d for patients with extensive prior treatment because, in the 19 mg/m(2)/d cohort, two patients had dose-limiting toxicities (one with grade 3 vomiting, diarrhea, and asthenia and one with elevated transaminases) and three patients required dose reductions. For minimally pretreated patients, in the 24 mg/m(2)/d cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m(2)/d as the maximum acceptable dose. Immunologic studies did not show any consistent trend toward immunosuppression. Temsirolimus exposure increased with dose in a less than proportional manner. Terminal half-life was 13 to 25 hours. Sirolimus-to-temsirolimus exposure ratios were 0.6 to 1.8. A patient with non-small cell lung cancer achieved a confirmed partial response, which lasted for 12.7 months. Three patients had unconfirmed partial responses; two patients had stable disease for >/=24 weeks. CONCLUSION: Temsirolimus was generally well tolerated on this intermittent schedule. Encouraging preliminary antitumor activity was observed.

Severe, late-onset graft-versus-host disease in a liver transplant recipient documented by chimerism analysis.

A 52-year-old liver transplant recipient presented 8 months after transplantation with oral thrush, then 3 days later with oral ulcers and a diffuse rash, and 5 days later with an acutely reduced white blood cell count, rash, fever, and diarrhea. Bone marrow biopsy revealed severe aplasia. Although graft-versus-host disease (GVHD) was considered, the late onset of these symptoms was felt to render this etiology unlikely because GVHD usually occurs 2 to 6 weeks after transplantation. All potentially myelosuppressive medications were discontinued, and the patient was treated with high doses of hematopoietic growth factors. Because his symptoms continued, chimerism analysis was performed, which indicated that 96% of the peripheral blood mononuclear cells were of liver-donor origin. Ultimately, the patient underwent an allogeneic peripheral blood hematopoietic progenitor cell transplant from a human leukocyte antigen-identical brother, but he died 5 days after transplantation of overwhelming Candida kruseii infection. To our knowledge, this is the first chimerism-analysis-documented case of severe acute GVHD presenting so late after liver transplantation. It is of note that the patient had no known risks for GVHD in that he was relatively young and shared only one major human leukocyte antigen with his donor. Consideration should be given to GVHD as a cause of bone marrow aplasia at any time after organ transplantation. Storage of cell pellets from all transplant recipients and donors is highly recommended to facilitate the diagnostic evaluation.

Clinical significance of recipient antibodies to stem cell donor mismatched class I HLA antigens.

A stem cell transplant candidate whose best-matched related donor had a mismatch for A68 by virtue of the patient's maternal human leukocyte antigen A/B (HLA-A/B) recombinant haplotype, was referred to Wilford Hall Medical Center for transplantation. She was determined prior to transplant to have a high-titered antibody to that HLA type and to several crossreactive antigens (A2 and A24). When she initially failed to engraft, plasmapheresis was tried three times with no effect on the antibody titer. Subsequently, plasmapheresis followed by intravenous immunoglobulin treatment and retransplant completely eliminated the donor-specific antibody. Engraftment occurred, and several weeks after the second transplant antibodies to A68 could no longer be detected although the antibodies to other HLA types were still present. This case report should serve to remind stem cell transplant programs of the importance of checking for the presence of recipient antibodies to donor-mismatched antigens and suggests that patients with such antibodies be treated prior to transplant.

Langerhans cell histiocytosis patients have HLA Cw7 and DR4 types associated with specific clinical presentations and no increased frequency in polymorphisms of the tumor necrosis factor alpha promoter.

BACKGROUND: Current theory on the etiology of Langerhans cell histiocytosis (LCH), formerly Histiocytosis-X, is that abnormality(ies) of the immune system are responsible for dysregulation of Langerhans cells (LC) in patients' lesions. Among the known abnormalities in LCH patients are increased amounts of tumor necrosis factor alpha (TNF-alpha) and other cytokines in the lesions. PROCEDURE: We investigated the human leukocyte antigen (HLA) phenotypes of 29 patients and 37 healthy family members to determine if any haplotypes segregate with the presence or locations of the disease. The lymphocyte subsets for 22 patients and 11 family members were also determined. RESULTS: Patients with single bone, multiple bone, or multi-system LCH had different relative proportions of HLA types. Patients presenting with single bone disease had an especially high frequency of the DR4 type. In this patient group, every Caucasian patient had either Cw7 or DR4. Lymphopenia was documented in patients who had been off therapy as well as those who only had surgical curetage of their lesions. Family members also had low numbers of T lymphocytes. There were fewer mutations of the TNF-alpha promoter in patients than in the general population. CONCLUSIONS: Although there is an increased percentage of LCH patients with DR4 and/or Cw7 there was also an increased prevalence of this antigen as well as lymphopenia among unaffected family members. Additional genetic and/or environmental factors are necessary to explain this association. TNF-alpha promoter mutations are not responsible for the increased production of this cytokine.