Abdelhamid Liacini

The p75 neurotrophin receptor is a central regulator of glioma invasion.

The invasive nature of cancers in general, and malignant gliomas in particular, is a major clinical problem rendering tumors incurable by conventional therapies. Using a novel invasive glioma mouse model established by serial in vivo selection, we identified the p75 neurotrophin receptor (p75NTR) as a critical regulator of glioma invasion. Through a series of functional, biochemical, and clinical studies, we found that p75NTR dramatically enhanced migration and invasion of genetically distinct glioma and frequently exhibited robust expression in highly invasive glioblastoma patient specimens. Moreover, we found that p75NTR-mediated invasion was neurotrophin dependent, resulting in the activation of downstream pathways and producing striking cytoskeletal changes of the invading cells. These results provide the first evidence for p75NTR as a major contributor to the highly invasive nature of malignant gliomas and identify a novel therapeutic target.

The dilemma of DQ HLA-antibodies.

Accurate identification of antibody reactivity against HLA-DQ antigens was difficult by using the old serological assays because of the strong linkage disequilibrium between HLA-DR and HLA-DQ (the usual inheritance of a certain HLA-DR molecule that ties together with the same DQ molecule within a racial group). The accurate and precise identifications of anti-HLA-antibodies of DQ specificities were made possible with the introduction of multiplex-bead arrays (Luminex), using single antigen bead (SAB) assay. The SAB assay is also considered today to be the most sensitive and specific method for alloimmunization assessment even for the low titer anti-HLA-antibodies. However, it is becoming clear that the detection of the HLA antibodies by SAB is not absolutely perfect due to the variation in densities, conformations and orientations of the antigen coated beads. Unlike HLA-DR, the HLA-DQ antigens are made of two polymorphic chains, both (alpha and beta chains) can contribute to the process of immunization individually or jointly. Routine SAB testing approach, which assigns the specificities based on beta chains and ignores the contribution of the DQα chains, can lead to erroneous DQ-antibody assignments. Therefore, it is important to recognize both the peculiarity of the HLA-DQ antigens as well as the nature of the assay format used in order to reach the correct antibody assignments. Erroneous donor specific antibodies (DSA) assignment may lead to denial of an otherwise immunologically compatible organ transplant, or exposing transplant recipients to unnecessary investigations or immunosuppression. The following two patients presented with HLA-antibodies against DQ antigens (anti-DQ-Abs) highlight these two scenarios.

Persistent immune-tolerance to non-inherited maternal antigen (NIMA) allows successful kidney transplantation in regraft patient: Case report

Kidney transplantation is the therapy of choice for patients with end stage renal disease. Graft survival is optimal when donor and recipient are fully match for the human leukocyte antigens (HLA), however due to the high degree of polymorphism of HLA, in most situation, this is not possible. Therefore haploidentical (partially matched) siblings, parents or off-spring are considered as potential donor. The patient inherits the maternal HLA-antigen (IMA) from the mother and paternal antigen (IPA) from the father. Figure 1 illustrates how a parent or sibling can share one haplotypes with the recipient and Abstract

Using Human Cytomegalovirus Glycoproteins to Prevent Graft versus Host Disease through Downregulation of Major Histocompatibility Complex Class I and Class II: A Novel Approach

Graft Versus Host Disease (GVHD) is an immune-mediated disease occurs as a complication of allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Differences between donor and recipient Major Histocompatibility Complex (MHC) antigens initiate the disease. The immunocompetent cells of the donor recognize the cells of the immunocompromised host as non-self, thus commencing an immune response against them. nThe human Cytomegalovirus (hCMV) is a member of the herpesvirus family that has developed strategies to escape the immune surveillance and defense system via encoding a series of glycoproteins that down regulate host MHC antigens. The Unique Short (US) hCMV glycoproteins US2, US3, US6, US10 and US11 have shown variable capabilities to downregulate MHC class I and II. Theoretically, these capabilities could be utilized to downregulate the expression of host MHC antigens, thus inhibiting the allograft recognition and the subsequent immune response, which would prevent GVHD. In this systematic review, 620 literatures have been identified through a PubMed, Epistemonikos, and Google Scholar search. An inclusion criterion has been applied to these studies, of which 27 have been selected. nThis review found that the hCMV glycoproteins act as partner to downregulate MHC class I and class II, CMV glycoproteins regulate destruction of class I MHC molecules, and degrade MHC class II. nThe Preferred Reporting Items for Systematic Reviews (PRISMA) Statement has been used to increase the quality of the review, and thus a Population Intervention Comparison Outcome Study design (PICOS) model has been formulated. nThe findings of this research could be further studied and validated to offer an alternative approach to the current pharmacological preventive measures of GVHD, possibly without compromising patients’ immunity.

Small G-protein Rnd3/RhoE is expressed in brain cancer and affects glioma morphology, motility and invasion

Malignant astrocytomas are highly invasive neoplasms infiltrating diffusely into regions of normal brain. Migration or invasion of tumor cells into normal tissue is a principal cause of mortality and is thought to be a multi-factorial process, consisting of cell interaction with ECM and adjacent cells, as well as accompanying biochemical processes supportive of active cell movement. Rho family members are known to regulate malignant transformation motility and invasion of cancer cells, but the clinicopathological significance of Rnd3 remains unclear. We evaluated the protein expression level of RhoE in gliomas tissues, cell lines and brain tumor initiating stem cells (BTSCs). Results showed that the expression of RhoE was significantly higher in patients with highly invasive gliomas. Next, we constructed a mammalian expression plasmid containing human RhoE and ectopically expressed it in U87. Ectopic expression of RhoE was found to induce membrane ruffle formation, increased migration and invasion both in vitro and in vivo and altered the relative levels of GTP-bound Rac1 and RhoA. Finally RhoE siRNA in the glioma cell line U251 inhibited cell invasion in vitro. In conclusion, the expression of RhoE appears to have a role in the pathogenesis of gliobstoma multiforme.

Ex-vivo expanded human NK cells mediate cytotoxicity and cytokine release against allogeneic cancer cell line by direct recognition and antibody directed cellular cytotoxicity: therapeutic potential use of NK cells for blood and solid tumors

Implementation of NK cell therapy is faced by several obstacles: the small number of NK cells in peripheral blood and the difficulties regarding production of effective cytolytic NK cells. We carried out this pilot study to determine if NK cells could be expanded and their degranulation, cytokines release abilities in response to allogeneic tumor target by direct cytotoxitiy and by antibody-mediated cellular cytotoxicity can be achieved.