Fracture Healing Is Delayed in Immunodeficient NOD/scid‑IL2Rγcnull Mice.

Following bone fracture, the repair process starts with an inflammatory reaction at the fracture site. Fracture healing is disturbed when the initial inflammation is increased or prolonged, whereby, a balanced inflammatory response is anticipated to be crucial for fracture healing, because it may induce down-stream responses leading to tissue repair. However, the impact of the immune response on fracture healing remains poorly understood.

Selectivity of C3-opsonin targeted complement inhibitors: A distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated cell lysis due to deficiency of GPI-anchored complement regulators. Blockage of the lytic pathway by eculizumab is the only available therapy for PNH patients and shows remarkable benefits, but regularly yields PNH erythrocytes opsonized with fragments of complement protein C3, rendering such erythrocytes prone to extravascular hemolysis. This effect is associated with insufficient responsiveness seen in a subgroup of PNH patients.

Comparative Analysis of Novel Complement-Targeted Inhibitors, MiniFH, and the Natural Regulators Factor H and Factor H-like Protein 1 Reveal Functional Determinants of Complement Regulation.

The serum proteins factor H (FH), consisting of 20 complement control protein modules (CCPs), and its splice product FH-like protein 1 (FHL-1; consisting of CCPs 1-7) are major regulators of the alternative pathway (AP) of complement activation. The engineered version of FH, miniFH, contains only the N- and C-terminal portions of FH linked by an optimized peptide and shows ∼ 10-fold higher ex vivo potency. We explored the hypothesis that regulatory potency is enhanced by unmasking of a ligand-binding site in the C-terminal CCPs 19-20 that is cryptic in full-length native FH.

Time-dependent effects of clinical predictors in unrelated hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation is a multifactorial process. Some of the predictors exhibit time-dependent effects. We present a systematic analysis and description of selected clinical predictors influencing outcome in a time-dependent manner based on an analysis of registry data from the German Registry for Stem Cell Transplantation.

Congenital CD59 Deficiency.

The severe clinical symptoms of inherited CD59 deficiency confirm the importance of CD59 as essential complement regulatory protein for protection of cells against complement attack, in particular protection of hematopoietic cells and human neuronal tissue. Targeted complement inhibition might become a treatment option as suggested by a case report. The easy diagnostic approach by flow cytometry and the advent of a new treatment option should increase the awareness of this rare differential diagnosis and lead to further studies on their pathophysiology.

Leukemic progenitor cells are susceptible to targeting by stimulated cytotoxic T cells against immunogenic leukemia-associated antigens.

Leukemic stem cells (LSC) might be the source for leukemic disease self-renewal and account for disease relapse after treatment, which makes them a critical target for further therapeutic options. We investigated the role of cytotoxic T-lymphocytes (CTL) counteracting and recognizing LSC. Leukemia-associated antigens (LAA) represent immunogenic structures to target LSC.

Crucial role of IL1beta and C3a in the in vitro-response of multipotent mesenchymal stromal cells to inflammatory mediators of polytrauma.

Multipotent mesenchymal stromal cells (MSC) exert immune-modulatory effects and support tissue regeneration in various local trauma models. In case of a polytrauma, high amounts of danger-associated molecular patterns are released, leading to a systemic increase of inflammatory mediators. The influence of such a complex inflammatory microenvironment on human MSC is mainly unknown so far.

Successful use of eculizumab for treatment of an acute hemolytic reaction after ABO-incompatible red blood cell transfusion.

Background: Transfusion of ABO major-incompatible red blood cells (RBCs) can activate the complement system and can cause severe and even lethal acute hemolytic reactions. The activation of the complement system with formation of C3a and C5a (anaphylatoxins) and the release of hemoglobin from the lysed RBCs are thought to mediate clinical signs like fever, hypotension, pain, and acute renal failure. Therapeutic inhibition of the complement cascade in case of ABO-incompatible RBC transfusion would be desirable to ameliorate the signs and symptoms and to improve the outcome of the reaction.

Liver abscess complicated by diaphragm perforation and pleural empyema leads to the discovery of interleukin-1 receptor-associated kinase 4 deficiency.

Interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency predisposes to severe invasive bacterial infections in infancy and early childhood, often with a fatal course caused by a defect in Toll-like receptor and interleukin-1 receptor signaling. Despite severe invasive infections, acute phase responses are often diminished. We report the successful treatment of a child with multiple liver abscesses, diaphragm perforation and pleural empyema, accompanied by strong acute phase responses as a unique presentation of IRAK-4 deficiency.

B-CLL cells acquire APC- and CTL-like phenotypic characteristics after stimulation with CpG ODN and IL-21.

CpG oligodeoxynucleotides (CpG) and IL-21 are two promising agents for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Recently, we reported that the combination of CpG and IL-21 (CpG/IL-21) can induce granzyme B (GrB)-dependent apoptosis in B-CLL cells. Here, we demonstrate that treatment of B-CLL cells with CpG and IL-21 results in the development of antigen-presenting cell (APC)-like cells with cytotoxic features.

A new blood group antigen is defined by anti-CD59, detected in a CD59-deficient patient.

Background: CD59 is a cell surface glycoprotein of approximately 20 kDa limiting the lytic activity of the terminal complement complex C5b-9. Although CD59 is known as a red blood cell (RBC) antigen defined by monoclonal antibodies, it so far has not been identified as a blood group antigen, since the description of a human alloantibody was missing. In this study we show the presence of an anti-CD59 in a patient affected by a homozygous CD59 deficiency.

High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis.

To validate current donor selection strategies based on previous international studies, we retrospectively analyzed 2646 transplantations performed for hematologic malignancies in 28 German transplant centers. Donors and recipients were high resolution typed for HLA-A, -B, -C, -DRB1, and -DQB1. The highest mortality in overall survival analysis was seen for HLA-A, -B, and DRB1 mismatches.

TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds.

Proper activation of macrophages (Mφ) in the inflammatory phase of acute wound healing is essential for physiological tissue repair. However, there is a strong indication that robust Mφ inflammatory responses may be causal for the fibrotic response always accompanying adult wound healing. Using a complementary approach of in vitro and in vivo studies, we here addressed the question of whether mesenchymal stem cells (MSCs)-due to their anti-inflammatory properties-would control Mφ activation and tissue fibrosis in a murine model of full-thickness skin wounds.

Second allograft for hematologic relapse of acute leukemia after first allogeneic stem-cell transplantation from related and unrelated donors: the role of donor change.

Purpose: To evaluate the role of a second allogeneic hematopoietic stem-cell transplantation (HSCT2) given for relapsed acute leukemia (AL) after related or unrelated first hematopoietic stem-cell transplantation (HSCT1) and to analyze the role of donor change for HSCT2 in both settings.

Patients And Methods: We performed a retrospective registry study on 179 HSCT2s given for relapse after HSCT1 from matched related donors (n = 75) or unrelated donors (n = 104), using identical or alternative donors for HSCT2. Separate analyses were performed according to donor at HSCT1.

Molecular basis of two novel and related high-prevalence antigens in the Kell blood group system, KUCI and KANT, and their serologic and spatial association with K11 and KETI.

Background: The numerous antigens in the Kell blood group system result from missense nucleotide changes in KEL. Antibodies to antigens in this system can be clinically important. We describe six probands whose plasma contained antibodies to high-prevalence Kell antigens and discuss their relationship.

TNFA promoter alleles--frequencies and linkage with classical HLA genes in a South German Caucasian population.

The tumor necrosis factor alpha (TNFA) promoter region exhibits several polymorphisms, which have been hypothesized to influence gene expression, thereby associating positively or negatively with inflammatory conditions. Many studies have focused on single nucleotide polymorphisms (SNPs) taking not into account additive or inverse effects between different SNPs. We typed 1,021 healthy Caucasian volunteer stem cell donors for their TNFA promoter as well as their HLA-A,-C,-B,-DRB1 loci.

Drugs that inhibit complement.

The complement system is an important part of the innate immune system. Complement plays a crucial role in the pathophysiology of many disorders. Despite the pivotal role of the complement system, an approved targeted inhibitor of a complement factor became available only recently.

Paroxysmal nocturnal haemoglobinuria treatment with eculizumab is associated with a positive direct antiglobulin test.

Background/objectives: Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by intravascular haemolysis with a negative direct antiglobulin test (DAT). Eculizumab is a humanized monoclonal antibody that inhibits complement component C5 and is approved for PNH treatment. Recent publications demonstrated that some patients with PNH develop a positive DAT during eculizumab treatment.

Automatic interface-controlled apheresis collection of stem/progenitor cells: results from an autologous donor validation trial of a novel stem cell apheresis device.

Background: Cryopreserved hematopoietic progenitor cells collected by apheresis from granulocyte-colony-stimulating factor with or without chemotherapy-mobilized patients have become the preferred type of autograft to support treatment of diseases amenable to high-dose chemotherapy. A novel apheresis system, the Spectra Optia v.5.

Six years' experience performing RHD genotyping to confirm D- red blood cell units in Germany for preventing anti-D immunizations.

Background: Red blood cell (RBC) units of D+ donors are falsely labeled D- if regular serologic typing fails to detect low D antigen expression or chimerism. The limitations of serology can be overcome by molecular typing.

Study Design And Methods: In January 2002, we introduced a polymerase chain reaction (PCR)-based assay for RHD as a routine test for first-time donors who typed D- by serologic methods including the indirect antiglobulin test.

Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia.

We analyzed the outcome of 692 patients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were peripheral blood progenitor cell (PBPC) grafts, and 558 were bone marrow (BM) grafts. Rates of hematopoietic recovery and grades 2 to 4 chronic graft-versus-host disease (GVHD) were similar after PBPC and BM transplantations regardless of age at transplantation.