Graft invariant natural killer T-cell dose predicts risk of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

Invariant natural killer T (iNKT) cells are powerful immunomodulatory cells that in mice regulate a variety of immune responses, including acute GVHD (aGVHD). However, their clinical relevance and in particular their role in clinical aGVHD are not known. We studied whether peripheral blood stem cell (PBSC) graft iNKT-cell dose affects on the occurrence of clinically significant grade II-IV aGVHD in patients (n = 57) undergoing sibling, HLA-identical allogeneic HSCT. In multivariate analysis, CD4^– iNKT-cell dose was the only graft parameter to predict clinically significant aGVHD. The cumulative incidence of grade II-IV aGVHD in patients receiving CD4^– iNKT-cell doses above and below the median were 24.2% and 71.4%, respectively (P = .0008); low CD4^– iNKT-cell dose was associated with a relative risk of grade II-IV aGVHD of 4.27 (P = .0023; 95% CI, 1.68-10.85). Consistent with a role of iNKT cells in regulating aGVHD, in mixed lymphocyte reaction assays, CD4^– iNKT cells effectively suppressed T-cell proliferation and IFN- secretion in a contact-dependent manner. In conclusion, higher doses of CD4^– iNKT cells in PBSC grafts are associated with protection from aGVHD. This effect could be harnessed for prevention of aGVHD (read more).

Proteinuria after kidney transplantation

The prevalence of proteinuria at 1 year after renal transplantation ranges between 11% and 45% and is even higher in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). Two main mechanisms can lead to proteinuria: an inadequate reabsorption of small proteins from proximal tubular cells damaged by ischemia-reperfusion injury, rejection, or toxic agents (tubular proteinuria) or an increased passage of albumin and/or protein with higher molecular weight (MW) because of a disruption of glomerular barrier caused by recurrent or de novo glomerulonephritis, transplant glomerulopathy, chronic rejection, or CNI toxicity (glomerular proteinuria). Proteinuric patients have worse patient and graft survival rates in comparison to non proteinuric patients. The amount of proteinuria is a reliable predictor of the allograft outcome. However, even microalbuminuria may be associated with a poor outcome. Treatment of proteinuria mainly rests on the management of the etiologic cause. Inhibitors of renin-angiotensin system (RAS) are useful in reversing microalbuminuria and can reduce proteinuria, but their efficacy in interfering with patient or graft survival is not demonstrated (read more).

HHV-6B is frequently found in the gastrointestinal tract in kidney transplantation patients

In immunosuppressed patients human herpesvirus 6 (HHV-6) reactivations are common. The aim of the study was to determine to which extent HHV-6 can be found in the gastrointestinal tract in kidney transplant recipients and in patients on chronic dialysis. The HHV-6 and cytomegalovirus (CMV) examinations were performed on gastro duodenal and colon biopsy specimens obtained from 81 kidney transplant recipients and on 46 chronic dialysis patients. The HHV-6 and CMV were demonstrated by immunohistochemistry detecting both HHV-6A and HHV-6B, and CMV-specific antigens. The HHV-6B-positive cells, were found in gastroduodenal biopsy specimens from 34% of the transplant recipients and 28% of the patients on chronic dialysis, CMV-positive cells were found in specimens from 53% of the transplant recipients and 28% of the patients on chronic dialysis. The HHV-6B positive cells were found in the colonic mucosa specimens from 36% of the transplant recipients and 22% of the patients on chronic dialysis, CMV-positive cells were found in specimens from 36% of the transplant recipients and 17% of the patients on chronic dialysis. The HHV-6B positive cells were found equally often in the gastroduodenal as in the colorectal mucosa. The HHV-6B positive cells as well as CMV positive cells were simultaneously found in every fifth of transplant recipients (read more).

Human leukocyte antigen epitope analysis to assess complement- and non-complement-binding donor-specific antibody repertoire in a pediatric heart transplant recipient.

This case report summarizes the spectrum of anti-human leukocyte antigen (HLA) antibody reactivity determined by single-allele Luminex immunoglobulin G and C1q binding assays before transplant, during an episode of antibody-mediated rejection (AMR), and following treatment in a sensitized pediatric heart transplant (Tx) recipient. We were able to discriminate between complement- and non-complement-binding epitope-specific antibodies present against a single donor antigen (HLA-A2) during the progression of AMR and its resolution. Our findings illustrate the usefulness of determining antibody specificities against epitopes using various Luminex-based assays (read more)

Adsorption of chain type–specific ABO antibodies on Sepharose-linked A and B tetrasaccharides

BACKGROUND: Antigen-specific removal of anti-A and anti-B on immunoadsorption columns carrying the blood group A and B trisaccharides is one important component of some protocols used in ABO-incompatible organ transplantation. Because ABO antibodies exist requiring parts of the core saccharide chain for binding, the anti-A and -B–binding capacity of individual and combined, Sepharose-linked Types 1 through 4 A and B tetrasaccharides with that of the A and B trisaccharides was compared.

STUDY DESIGN AND METHODS: Sepharose-linked A and B tri- and tetrasaccharides were used to adsorb anti-A and -B from pooled blood group O serum. Remaining chain type–specific anti-A and -B were detected and quantified in enzyme-linked immunosorbent assays using wells coated with neoglycoproteins or recombinant mucins carrying A and B determinants on defined core saccharide chains.

RESULTS: Significantly more anti-A Type 3- and 4-specific immunoglobulin (Ig)G remained after adsorption on the A trisaccharide and the A Type 1 and A Type 2 tetrasaccharide than after adsorption on the A Types 3 and 4 tetrasaccharides. Selective adsorption of chain type–specific IgG anti-B was detected on Sepharose-linked B tetrasaccharides. In contrast, there were no chain type–specific IgM anti-A or -B. A combination of the A or B tetrasaccharides adsorbed a larger fraction of the IgG anti-A and -B repertoires than the corresponding trisaccharides.

CONCLUSION: There are chain type–specific anti-A and anti-B IgG, and an adsorber based on a combination of Types 1 through 4 A or B tetrasaccharides will be a more efficient adsorber than an adsorber based on the A or B trisaccharides (read more).

Interaction of the humoral immune system with peptides presented by class I major histocompatibility (MHC) complexes [B Lymphocyte Signaling and Transcription]

Antibodies usually bind to unprocessed antigens, while cytotoxic T cells react with peptides derived from intracellular antigens when presented by class I major histocompatibility (MHC) complexes. We screened human sera for antibodies reacting specifically with the influenza matrix protein (IMP) derived peptide (58-66) displayed by HLA-A*0201 complexes by ELISA. Among blood donors, high-titered HLA-A*0201/IMP (58-66) complex-specific IgG antibodies were detected in HLA-A*0201- females with a history of pregnancies. Extended analyses of specificity indicated that these antibodies interacted peptide-specific with the MHC complex. No antibodies were detected in HLA-A*0201+ female or male blood donors. In another cohort of 218 females on delivery, only HLA-A*0201- mothers had HLA-A*0201/IMP (58-66) antibodies, which were also detected in the cord blood of the newborns, demonstrating that HLA-A*0201/ IMP58-66 antibodies are produced in HLA-A*0201- mothers and enter the fetal blood system. Refolding the peptide IMP (58-66) with all HLA-A, -B and -Cw alleles of the mothers and newborns revealed, that these antibodies are allo-reactive and are binding in some cases to the peptide displayed by a MHC allele of an offspring. Therefore allo-MHC/IMP (58-66) antibodies might provide immunity in HLA-disparate pregnancies. These antibody responses specific to a peptide displayed by a class I MHC complex opens a new dimension of interactions between the cellular and humoral immune system (read more).

Mesenchymal Stromal Cells: A New Tool against Graft-versus-Host Disease?

Mesenchymal stromal cells (MSCs) represent a heterogeneous subset of multipotent cells that can be isolated from several tissues including bone marrow and fat. MSCs exhibit immunomodulatory and anti-inflammatory properties that prompted their clinical use as prevention and/or treatment for severe graft-versus-host disease (GVHD). Although a number of phase I-II studies have suggested that MSC infusion was safe and might be effective for preventing or treating acute GVHD, definitive proof of their efficacy remains lacking thus far. Multicenter randomized studies are ongoing to more precisely assess the impact of MSC infusion on GVHD prevention/treatment, whereas further research is performed in vitro and in animal models with the aims of determining the best way to expand MSCs ex vivo as well as the most efficient dose and schedule of MSCs administration. After introducing GVHD, MSC biology, and results of MSC infusion in animal models of allogeneic hematopoietic cell transplantation, this article reviews the results of the first clinical trials investigating the use of MSC infusion as prevention or treatment of GVHD (read more).