Ulcerative colitis (UC) and Crohn's disease (CD) are common inflammatory bowel diseases producing intestinal inflammation and tissue damage. Although emerging evidence suggests these diseases are distinct, ϳ10% of patients remain classified as indeterminate inflammatory bowel disease even after invasive colonoscopy intended for diagnosis. A molecular diagnostic assay using a clinically accessible tissue would greatly assist in the classification of these diseases. In the present study we assessed transcriptional profiles in peripheral blood mononuclear cells from 42 healthy individuals, 59 CD patients, and 26 UC patients by hybridization to microarrays interrogating more than 22,000 sequences. Supervised analysis identified a set of 12 genes that distinguished UC and CD patient samples with high accuracy. The alterations in transcript levels observed by microarray were verified by real-time polymerase chain reaction. The results suggest that a peripheral blood mononuclear cell-based gene expression signature can provide a molecular biomarker that can complement the standard diagnosis of UC and CD.

The chemokine stromal cell–derived factor 1 (SDF-1) is essential for perinatal viability, B lymphopoiesis, and bone marrow myelopoiesis, and is a potent monocyte and T-lymphocyte chemoattractant. Interactions of SDF-1 with its receptor CXCR4 have been implicated in CD34+ cell migration and homing. Here it is shown that human SDF-1β (hSDF-1β) alone secreted by hSDF-1β–transduced tumor cells promotes efficacious antitumor responses. The murine C1498 leukemia and B16F1 melanoma models have been studied. For expression of hSDF-1β by tumor cells (SDF-tumor cells), packaging cell lines secreting retroviruses encoding hSDF-1β have been used. The results demonstrate that 50% (B16F1) and 90% (C1498) of naive mice injected with SDF-tumor cells reject their tumors. Prophylactic vaccination of naive mice with irradiated SDF-tumor cells leads to systemic immunity, and therapeutic vaccination leads to cure of established tumors. Mice that previously rejected live SDF-tumor cells are immune to the rejected tumor but susceptible to another tumor and have in vitro tumor-specific cytotoxic T lymphocyte (CTL) activity. SDF-tumor cells are not rejected by immunodeficientscid mice. Immunohistochemistry shows significant infiltration of SDF-1 tumors by T cells, and in vivo T-cell depletion studies indicate that CD4+ T cells are required for SDF-mediated tumor rejection. In conclusion, the present data suggest that SDF-1/CXCR4 interactions have the potential to regulate efficacious antitumor immune responses; exploitation of these interactions may lead to novel therapeutic interventions.

Major mechanisms underlying poor immune responses to autologous tumorassociated antigens are overwhelming tumor kinetics and the absence of effective T-cell costimulation by antigen-presenting cells. To address these issues, leukemia and lymphoma mice were treated with the combination of chemotherapy and systemic immunotherapy with recombinant soluble murine B7-immunoglobulin G (IgG) molecules. In this report, 3 murine models were used, a radiationinduced SJL acute myeloid leukemia, a transplantable spontaneous SJL lymphoma, and the C57BL/6 EL-4 thymic lymphoma. Various treatment modalities were evaluated: single treatments with either B7-IgG or chemotherapy as well as combination therapies. The results demonstrate the following: (1) in all tumor models, the combination of chemotherapy and soluble B7-IgGs is more potent than either therapy alone, leading to cure of tumorbearing animals; (2) the therapeutic responses are T-cell-dependent, because combined therapy is not efficacious in severe combined immunodeficient mice; (3) the rejection of tumor cells leads to the development of tumor-specific immunity, because cured mice are immune to the rejected tumor but not to a different syngeneic tumor; and (4) 51 IntroductionMajor recent discoveries that have drastically modified the nature of T-cell-directed immunotherapy in cancer are the cloning of several tumor-associated antigens (TAAs) that elicit autologous cytotoxic T-cell responses 1,2 and the discovery of new molecules and pathways involved in T-cell activation and costimulation. 3,4 This knowledge has guided the design of numerous preclinical and clinical studies that, in turn, have generated remarkable insight into the mechanisms controlling host responses to cancer cells. Thus, it is now accepted that few spontaneous tumors are immunogenic, but most, if not all, are antigenic. 5,6 However, what ultimately determines the outcome of an endogenous antigen encounter is the context in which that particular antigen is presented to T cells. 7,8 In the absence of danger signals that accompany tissue destruction and inflammation (typically observed during viral infection), the outcome is immune ignorance. 9,10 At the level of antigenpresenting cell (APC)-T-cell interactions, the local danger signals translate primarily into the up-regulation of T-cell costimulatory signals provided by APCs at the time of antigen presentation.Costimulation is defined as a signal necessary for optimal T-cell activation and survival delivered to T cells along with the T-cell receptor (TCR) signal, provided by APCs, ie, activated B cells, macrophages, and dendritic cells. 11,12 Over the years, the CD28/B7 T-cell costimulatory pathway has emerged as the key regulator of T-cell responses. The signal involves the interaction of the T-cell surface antigen CD28 with the members of the B7 family molecules B7.1 (CD80) and B7.2 (CD86) expressed on APCs. 13,14 Following a TCR-mediated signal, ligation of CD28 results in up-regulation of the interleukin 2 (IL-2)-receptor, increased IL-2 messe...

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