Diverse hematological malignancies including hodgkin-like lymphomas develop in chimeric MHC class II transgenic mice.

A chimeric HLA-DR4-H2-E (DR4) homozygous transgenic mouse line spontaneously develops diverse hematological malignancies with high frequency (70%). The majority of malignancies were distributed equally between T and B cell neoplasms and included lymphoblastic T cell lymphoma (LTCL), lymphoblastic B cell lymphoma (LBCL), diffuse large B cell lymphoma (DLBCL), the histiocyte/T cell rich variant of DLBCL (DLBCL-HA/T cell rich DLBCL), splenic marginal zone lymphoma (SMZL), follicular B cell lymphoma (FBL) and plasmacytoma (PCT). Most of these neoplasms were highly similar to human diseases. Also, some non-lymphoid malignancies such as acute myeloid leukemia (AML) and histiocytic sarcoma were found. Interestingly, composite lymphomas, including Hodgkin-like lymphomas, were also detected that had CD30(+) Hodgkin/Reed-Sternberg (H/RS)-like cells, representing a tumor type not previously described in mice. Analysis of microdissected H/RS-like cells revealed their origin as germinal center B cells bearing somatic hypermutations and, in some instances, crippled mutations, as described for human Hodgkin lymphoma (HL). Transgene integration in an oncogene was excluded as an exclusive driving force of tumorigenesis and age-related lymphoma development suggests a multi-step process. Thus, this DR4 line is a useful model to investigate common molecular mechanisms that may contribute to important neoplastic diseases in man.

Antigen presenting cells transfected with LMP2a RNA induce CD4+ LMP2a-specific cytotoxic T lymphocytes which kill via a Fas-independent mechanism.

Recent reports have demonstrated that EBV can be used as a target of specific CTL-based treatments in severe chronic EBV, immunoblastic B cell lymphoma and Hodgkin's disease (HD). Based upon the promising results form these in vivo studies, it has been suggested that an antigen-specific CTL-based immunotherapy may be of benefit in treating EBV-associated tumors such as HD and nasopharyngeal carcinoma (NPC) which express the potentially immunogenic antigens, LMP1 and LMP2a. Recent work form our group has demonstrated that LMP2a-specific CTLs may be generated in vitro using autologous antigen presenting cells which have been transfected with polyadenylated LMP2a RNA in the presence of a cationic lipid. In this study, we demonstrate that the presence of the lipid enhances dendritic cell (DC) transfection efficiency and appears to protect the intracellular LMP2a RNA from degradation by cellular RNAses. Significantly, these improvements resulted in the transfected DCs having a superior ability to stimulate autologous T cell proliferation. These LMP2a + DCs were used to stimulate LMP2a-specific effector cells which were predominantly a mixture of cytotoxic and helper CD4+ T cells. The molecular mechanisms whereby these CD4+ T cells lyzed their LMP2a-expressing targets was investigated and we show that, although expressing Fas ligand on their surface, LMP2a-specific CD4+ effector cells kill their targets using the Ca2+-dependent perforin/granzyme pathway which is the same mechanism used by CD8+ CTLs.