HLA class II upregulation during viral infection leads to HLA-DP-directed graft-versus-host disease after CD4+ donor lymphocyte infusion

CD8+ T cell–depleted (TCD) donor lymphocyte infusion (DLI) after TCD allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with a reduced risk of graft-versus-host disease (GVHD) while preserving conversion to donor hematopoiesis and antitumor immunity, providing a rationale for exploring CD4+ T cell–based immunotherapy for hematologic malignancies. Here, we analyzed the clinical course and specificity of T cell immune responses in 2 patients with acute myeloid leukemia (AML) who converted to full-donor chimerism but developed severe acute GVHD after prophylactic CD4+ DLI after 10/10-HLA–matched, but HLA-DPB1–mismatched TCD-alloSCT. Clonal analysis of activated T cells isolated during GVHD demonstrated allo-reactivity exerted by CD4+ T cells directed against patient-mismatched HLA-DPB1 molecules on hematopoietic cells and skin-derived fibroblasts only when cultured under inflammatory conditions. At the time of CD4+ DLI, both patients contained residual patient-derived T cells, including cytomegalovirus (CMV)-specific T cells as a result of CMV reactivations. Once activated by CMV antigens, these CMV-specific T cells could stimulate HLA-DPB1–specific CD4+ T cells, which in turn could target nonhematopoietic tissues in GVHD. In conclusion, our data demonstrate that GVHD after HLA-DPB1–mismatched CD4+ DLI can be mediated by allo-reactive HLA-DPB1–directed CD4+ T cells and that ongoing viral infections inducing HLA class II expression on nonhematopoietic cells may increase the likelihood of GVHD development. This trial is registered at http://www.controlled-trials.com/ISRCTN51398568/LUMC as #51398568. (read more)

The major histocompatibility complex: a model for understanding graft-versus-host disease

Acute graft-versus-host disease (GVHD) afflicts as much as 80% of all patients who receive an unrelated donor hematopoietic cell transplant (HCT) for the treatment of blood disorders, even with optimal donor HLA matching and use of prophylactic immunosuppressive agents. Of patients who develop acute GVHD, many are at risk for chronic GVHD and bear the burden of considerable morbidity and lowered quality of life years after transplantation. The immunogenetic basis of GVHD has been the subject of intensive investigation, with the classic HLA genetic loci being the best-characterized determinants. Recent information on the major histocompatibility complex (MHC) region of chromosome 6 as an important source of untyped genetic variation has shed light on novel GVHD determinants. These data open new paradigms for understanding the genetic basis of GVHD (read more)

Donation from old living donors: how safe is it?

As the rate of living kidney donor (LKD) transplantations increases, the selection of extended criteria donors such as old donors (>60–65 years) becomes more common. The pool of these old donors is probably wider than we think, especially if we tolerate a lower glomerular filtration rate (GFR) than the gold standard of 80 mL/min/1.73 m². Several important studies with large cohorts of living donors including old subjects have been published these last few years and give insights on the outcome in this subpopulation. The risk of death and end-stage renal disease (ESRD) is similar to that of matched controls from the general population. Post-donation GFR, as a result of glomerulopaenia, is lower in old than in younger donors but pre-donation as well as the rate of function loss is not different between young and old donors. Nearly 80% of donors over 60 have <60 mL/min GFR post-donation, the risk of cardiovascular mortality and progression to ESRD in the long term, as in the general population, is under question. Despite reduced renal function of the old kidney, the results of transplantation from an old living donor appeared to be equivalent to deceased transplantation from a younger donor. Finally, transplantation from an old living donor appeared to be a reasonably safe procedure for both the donor and the recipient and the age per se is certainly not a contraindication to donation (read more)

What do we know about adenovirus in renal transplantation?

Adenoviruses are common pathogens that have the potential to cause opportunistic infections with significant morbidity and mortality in immunocompromised hosts. The significance of adenoviral infection and disease is incompletely known in the setting of kidney transplantation. Reported adenovirus infections in renal transplant recipients have typically manifested as hemorrhagic cystitis and tubulointerstitial nephritis, less severe diseases than often seen in other solid organ transplant recipients (i.e. pneumonia, hepatitis and enteritis). The prevalent adenovirus subgroups associated with cystitis and nephritis are B1 and B2 with the serotypes 7, 11, 34, 35. However, disseminated or severe adenovirus infections, including fatal cases, have been described in renal transplant recipients. There is uncertainty regarding monitoring of and treatment of this virus. Although not supported by randomized clinical trials, cidofovir is used for the treatment of adenovirus disease not responding to reduction of immunosuppression (read more)

High-Dose Intravenous Immunoglobulin (IVIG) Adjuvant Therapy for Cell-Mediated Pancreas Transplant Rejection

Untreated pancreas transplant rejection is a barrier to long-term graft survival. Conventionally, cell-mediated rejection in pancreas transplantation can be mitigated by intravenous corticosteroids and rabbit antithymocyte globulin (rATG). In contrast to cellular rejection, antibody-mediated rejection requires anti-CD20 monoclonal antibodies, plasmapheresis, and intravenous immunoglobulin (IVIG). High-dose IVIG possesses broad anti-inflammatory properties, making it suitable for treating rejection. Herein, we report the first documented case of successful adjuvant therapy for pancreas transplant cell-mediated rejection using high-dose IVIG (read more)

Successful Engraftment in HLA-Mismatched Bone Marrow Transplantation Despite the Persistence of High-Level Donor-Specific Anti-HLA-DR Antibody

Graft failure remains the major complication after allogeneic stem cell transplantation. Presence of donor-specific anti–human leukocyte antigen (HLA) antibody (DSA) is not only a risk for graft failure mostly in cord blood transplantation (1), but also in other HLA mismatched related or unrelated stem cell transplantation. Here, we report successful engraftment after HLA mismatched unrelated bone marrow transplantation (BMT) in a patient with acute myeloid leukemia with myelodysplasia-related change, who had high-level anti-HLA-DR DSA... Intriguingly, in this case, severe skin and gut acute GVHD occurred on day +31 after transplantation, the period was just after the disappearance of DSA (Fig. 1). Previous reports suggested that incidence of acute GVHD was lower in patients with DSA compared with without DSA after cord blood transplantation. HLA-DR is usually expressed in activated T cells more than in resting T cells. It is therefore tempting to speculate that DSA may have a role in suppressing GVHD. Further investigation might be needed about the relationship between DSA, particularly against HLA-DR and GVHD (read more)

Relative Importance of HLA Mismatch and Donor Age to Graft Survival in Young Kidney Transplant Recipients

The American deceased-donor (DD) kidney allocation algorithm for children emphasizes the importance of younger donors and shorter waiting times over human leukocyte antigen (HLA) matching. We sought to compare the relative importance of donor age with that of HLA mismatching (MM) on graft survival. MethodsWe studied patients less than 21 years old recorded in the U.S. Renal Data System, who received a first transplant from a DD 5 years old or younger or from a living donor (LD). Using separate Cox proportional hazards models for DD and LD recipients, we estimated the adjusted 5-year probability of graft survival for each donor age–HLA MM combination and compared estimated graft survival across the different HLA MM–donor age combinations. ResultsBoth donor age and HLA MM were significantly associated with DD graft survival, whereas only HLA MM had a significant association with LD graft survival. Compared with DD grafts from less than 35-year-old 4–6 MM donors, survival was not significantly different for 0–1 and 2–3 MM grafts from 35- to 44-year-old donors or for 0–1 MM grafts from donors 45 years old or older. The most poorly matched grafts from the oldest LD had survival similar to or better than any DD. ConclusionsDonor age and HLA MM both play important roles in determining DD graft survival. The advantages of younger donors offset the disadvantages of poorer HLA matching, and better HLA matching offsets the disadvantages of older donor age (read more)

Very low residual concentrations of rituximab long after infusion still induce positive B-cell complement-dependent cytotoxicity-crossmatch.

Rituximab may induce positive B-cell complement-dependent cytotoxicity crossmatch (CDC-XM) in the absence of donor-specific antibodies, as we report in these 2 cases. We retrospectively assessed the in vitro concentration-effect relationship of rituximab in sera. B-cell CDC-XM results were positive only in the presence of rituximab, even with low concentrations (inferior to 1 μg/mL). Moreover, rituximab neutralization with increasing concentration of an anti-rituximab-idiotype monoclonal antibody progressively reduced B-cell lysis. In conclusion, measurement of rituximab content may be useful to identify sera at risk of misinterpretation in immunized patients (read more)