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Central nervous system acute lymphoblastic leukemia (CNS-ALL) is a major clinical problem. Prophylactic therapy is neurotoxic, and a third of the relapses involve the CNS. Increased expression of interleukin 15 (IL-15) in leukemic blasts is associated with increased risk for CNS-ALL. Using in vivo models for CNS leukemia caused by mouse T-ALL and human xenografts of ALL cells, we demonstrate that expression of IL-15 in leukemic cells is associated with the activation of natural killer (NK) cells. This activation limits the outgrowth of leukemic cells in the periphery, but less in the CNS because NK cells are excluded from the CNS. Depletion of NK cells in NOD/SCID mice enabled combined systemic and CNS leukemia of human pre-B-ALL. The killing of human leukemia lymphoblasts by NK cells depended on the expression of the NKG2D receptor. Analysis of bone marrow (BM) diagnostic samples derived from children with subsequent CNS-ALL revealed a significantly high expression of the NKG2D and NKp44 receptors. We suggest that the CNS may be an immunologic sanctuary protected from NK-cell activity. CNS prophylactic therapy may thus be needed with emerging NK cell-based therapies against hematopoietic malignancies.

Factor XI deficiency, an injury-related bleeding disorder, is rare worldwide but common in Jews in whom 2 mutations, Glu117Stop (type II) and Phe283Leu (type III), prevail. Mean factor XI activities in homozygotes for Glu117Stop and for Phe283Leu are 1 and 10 U/dL, respectively. Inhibitors to factor XI in patients with severe factor XI deficiency have been reported in a small number of instances. This study was undertaken to determine the prevalence of acquired inhibitors against factor XI in patients with severe factor XI deficiency, discern whether these inhibitors are related to specific mutations, and characterize their activity. Clinical information was obtained from unrelated patients with severe factor XI deficiency, and blood was analyzed for factor XI activity, inhibitor to factor XI, and causative mutations. Immunoglobulin G purified from patients with an inhibitory activity was tested for binding to factor XI, effects on activation of factor XI by factor XIIa and thrombin, and activation of factor IX by exogenous factor XIa. Of 118 Israeli patients, 7 had an inhibitor; all belonged to a subgroup of 21 homozygotes for Glu117Stop who had a history of plasma replacement therapy. Three additional patients with inhibitors from the United Kingdom and the United States also had this genotype and were exposed to plasma. The inhibitors affected factor XI activation by thrombin or factor XIIa, and activation of factor IX by factor XIa. The results imply that patients with a very low factor XI level are susceptible to development of an inhibitor following plasma replacement.

Abstract 2221 Neonatal alloimmune thrombocytopenia (NAIT) is a life-threatening bleeding disorder in the fetus/ neonate caused by maternal alloantibodies directed against fetal platelet antigens inherited from the father. Of the 21 allonatigens described up to date http://www.ebi.ac.uk/ipd/hpa/table2.html, the human platelet antigen (HPA) −1 defined as a leucine /proline polymorphism at residue 33 in b3 integrin is the immune-dominant antigen leading to severe NAIT. Immunization to HPA-1a occurs only in 10% of HPA-1bb pregnant women, 90% of them carrying histocompatibility leukocyte antigen (HLA) DRB3*0101. The aims of the present study were: 1. to prospectively study whether in addition to HLA DR B3*0101 there other potential HLA DR antigens involved in the immune process. 2. To analyse whether the response to IVIgG treatment correlates with maternal HLA DR genotype 3. to determine whether, anti HLA antibodies in addition to HPA1a antibodies, resulted in a more severe thrombocytopenia. We enrolled 21 pregnant women who had previously given birth to newborns with NAIT due to HPA1 incompatibility and had antibodies directed to their spouses HPA1 phenotype (leucine or proline polymorphism ) at the Sheba Medical Center from May 2001 to January 2011. The control group consisted of 21 women who delivered at term newborns with thrombocytopenia and a diagnosis of NAIT was ruled out. Twelve women of 21 (57%) in the study group carried both HLADRB3*0101 and DRB4*0101phenotype. But in none of the women in the control group such combination was detected. Interestingly is the observation that of 20 women who gave birth once more following IVIgG treatment, four did not respond to IVIgG and 3 (75%) of them harbor both DRB3*0101 and DRB4*0101. When lymphocytotoxic cross match analysis was performed in eighteen couples of the study group seven (39%) of them had positive lymphocytotoxic cross match. However the presence of both HLA and HPA1 antibodies against their partner phenotype did not affect platelets' counts in the newborn. Taken together we postulate that the presence of both HLADRB3*0101 and HLADRB4*0101 in the mother increases the risk of NAIT development when HPA1 incompatibility between the couples is found and can serve as a diagnostic tool. The presence of HLA antibodies against the spouse did not alter response to IgG treatment. Disclosures: No relevant conflicts of interest to declare.