Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells

Despite advances in immunosuppressive regimens, acute graft-versus-host disease remains a frequent complication of allogeneic hematopoietic cell transplantation. Pathogenic donor T cells are dependent on correct attachment of small GTPases to the cell membrane, mediated by farnesyl- or geranylgeranyl residues, which, therefore, constitute potential targets for graft-versus-host disease prophylaxis. A mouse model was used to study the impact of a farnesyl-transferase inhibitor and a geranylgeranyl-transferase inhibitor on acute graft-versus-host disease, anti-cytomegalovirus T-cell responses and graft-versus-leukemia activity. Treatment of mice undergoing allogeneic hematopoietic cell transplantation with farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor reduced the histological severity of graft-versus-host disease and prolonged survival significantly. Mechanistically, farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor treatment resulted in reduced alloantigen-driven expansion of CD4 T cells. In vivo treatment led to increased thymic cellularity and polyclonality of the T-cell receptor repertoire by reducing thymic graft-versus-host disease. These effects were absent when squalene production was blocked. The farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor did not compromise CD8 function against leukemia cells or reconstitution of T cells that were subsequently responsible for anti-murine cytomegalovirus responses. In summary, we observed an immunomodulatory effect of inhibitors of farnesyl-transferase and geranylgeranyl-transferase on graft-versus-host disease, with enhanced functional immune reconstitution. In the light of the modest toxicity of farnesyl-transferase inhibitors such as tipifarnib in patients and the potent reduction of graft-versus-host disease in mice, farnesyl-transferase and geranylgeranyl-transferase inhibitors could help to reduce graft-versus-host disease significantly without having a negative impact on immune reconstitution.     

Combination of sunitinib with anti‐tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy

Sunitinib, a protein tyrosine kinase inhibitor is the frontline therapy for renal and gastrointestinal cancers. We hypothesized that by virtue of its well documented tumor apoptosis and immune adjuvant properties, combination of Sunitinib with anti‐tumor immunotherapeutics will provide synergistic inhibition of tumor growth. Our study was designed to evaluate the impact of Sunitinib on immunotherapy mediated anti‐tumor immune responses and evaluate its efficacy as a combinatorial therapy with tumor targeted immunotherapeutic vaccination. Mice immunized with recombinant α‐lactalbumin, a lactation protein expressed on majority of breast tumors were treated with 1 mg of Sunitinib for seven consecutive days beginning (1) concurrently, on the day of α‐lactalbumin immunization or (2) sequentially, on day 9 after immunization. Ten‐day lymph nodes or 21 day spleens were tested by ELISPOT assays and flow cytometry to evaluate responsiveness to α‐lactalbumin immunization in presence of Sunitinib and distribution of cells involved in T cell antigen priming and proliferation in different lymphoid compartments. In addition, therapeutic efficacy of the α‐lactalbumin/ Sunitinib combination was evaluated by monitoring tumor growth in the 4T1 transplanted tumor model. Our studies reveal that concurrent administration of Sunitinib with active vaccination against a targeted tumor antigen inhibits priming to the immunogen due to a drastic decrease in CD11b+CD11c+ antigen presenting cells, leading to failure of vaccination. However, sequential delivery of Sunitinib timed to avoid the priming phase of vaccination results in the desired vaccination mediated boost in immune responses.     

Management und Kontrolle einer Influenzapandemie Konzeptionelle Überlegungen für einen deutschen Influenzapandemieplan

The World Health Organization (WHO) and the majority of the influenza experts assume that an influenza pandemic might reemerge again at any time. Therefore WHO has called upon all member states to set up a national pandemic preparedness plan. For Germany such a plan is long overdue. In order to gain as much time as possible early identification of the pandemic virus is of highest priority. Furthermore progression of a pandemic is influenced by the time needed to develop a subtype specific vaccine as well as by the vaccines availability. However, in case of a pandemic a shortage of vaccines and prophylactic pharmaceuticals cannot be avoided. Therefore, decisions have to be made in order to establish priorities concerning the vaccination and the prophylactic and/or therapeutic antimicrobial treatment of selected sub-populations. There is also a need to lay down measures ensuring the distribution of vaccines and antiviral drugs, adequate health care and ambulance service, and the organization of dignified funerals of the deceased. It is also necessary to enter into an early agreement with vaccine manufacturers on a guaranteed supply of respective batches of vaccine doses. In addition procedures should be established to allow an increase in vaccine production in case of a pandemic. There is also a need for early agreements with the manufacturers of antiviral agents and for a decision concerning the establishment of a national stockpile to guarantee an adequate supply. Some measures must already be taken in the inter-pandemic period. Those are: enhancement of surveillance and research, development of new vaccines and new methods of vaccine production, licensing of new vaccines in case of a pandemic and establishment of a national influenza committee. Problems like the effectiveness of antiepidemic measures, such as immigration control and the closing of schools, must be solved in advance of a pandemic.     

Biology-Driven Approaches to Prevent and Treat Relapse of Myeloid Neoplasia after Allogeneic Hematopoietic Stem Cell Transplantation

The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs.     

Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: a potent, orally active monocyclic beta-lactam inhibitor of human polymorphonuclear leukocyte elastase.

A series of potent and highly selective time-dependent monocyclic beta-lactam inhibitors of human polymorphonuclear leukocyte elastase (PMNE, EC 3.4.21.37) is described. The intrinsic potency of these compounds, as exemplified by L-680,833 (k(inactivation)/K(i) of 622,000 M-1.s-1), is reflected at the cellular level where it inhibits generation of the specific N-terminal cleavage product A alpha-(1-21) from the A alpha chain of fibrinogen by enzyme released from isolated polymorphonuclear leukocytes stimulated with fMet-Leu-Phe with an IC50 of 0.06 microM. The inhibitory activity of L-680,833 is also apparent in whole blood stimulated with A23187, where it inhibits formation of A alpha-(1-21) and PMNE-alpha 1-proteinase inhibitor complex formation with IC50 values of 9 microM. Pharmacokinetic studies indicate that after oral dosing L-680,833 is bioavailable in rats and rhesus monkeys. This oral bioavailability is reflected by the inhibition (i) of tissue damage elicited in hamster lungs by intratracheal instillation of human PMNE and (ii) enzyme released from human PMN stimulated after their transfer into the pleural cavity of mice. The properties of L-680,833 allow it to effectively supplement the activity of natural inhibitors of PMNE in vivo, suggesting that this type of low-molecular-weight synthetic inhibitor could have therapeutic value in diseases where PMNE damages tissue.     

Nutrient Composition of Bee Brood and its Potential as Human Food

Bee brood serves as a food source to humans in many countries although limited data exists concerning its nutrient composition. Bee brood (pupae and larvae) were analyzed for moisture, protein, fat, ash, fiber, minerals, amino acids, fatty acids, and vitamins. Bee brood was high in protein, fat, and carbohydrate. While low in calcium, bee brood was a good source of phosphorus, magnesium, potassium, and the trace minerals iron, zinc, copper, and selenium. In addition, bee brood was a good source of essential amino acids with methionine being first limiting. While bee brood contained none of the fat soluble vitamins (vitamins A, D, and E) it was a good source of most of the B-vitamins as well as vitamin C and choline. The fat was composed mostly of saturated and monounsaturated fatty acids with only 2.0% being polyunsaturated fatty acids.     

The role of ABO matching in platelet transfusion

Abstract: A prospective controlled trial was performed to determine whether the use of ABO-identical platelets from the start of treatment might provide higher post-transfusion platelet increments, reduce the number of platelet transfusions and ultimately delay the onset of refractoriness. Forty newly diagnosed patients with haematological diseases were randomized to receive either pooled ABO-identical platelets or pooled platelets unmatched for ABO group throughout their course. The corrected platelet count increments (CCI) were calculated for the first 25 transfusions of each patient and non-immune factors present at the time of each platelet transfusion were documented. The mean CCI for the first 25 transfusions in the ABO-identical group was significantly higher (6600 ±: 7900 SD) than that achieved with ABO unmatched platelets (5200 ±: 7900; p<0.01). The effect was most marked for the first 10 transfusions for each patient where the CCI was 64% higher in the ABO-identical group (8200 ±: 7500 vs 5000 ±: 8100; p<0.0002). Patients given ABO-identical platelets required only about half as many transfusions in the first 30 days (10 versus 17, p<0.05) or during the first admission (11 versus 21 p<0.01) as patients in the ABO-unmatched group. A smaller percentage of patients in the ABO-identical group became refractory (36% vs 75% p<0.03). The data suggest that patients requiring long-term platelet support should be transfused with ABO-identical platelets.