Stephan Grabbe

Tumor antigen presentation by epidermal antigen-presenting cells in the mouse : modulation by granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, and ultraviolet radiation

I‐A+ epidermal antigen‐presenting cells (APCs, Langerhans cells) have been shown to present tumor‐associated antigens (TAAs) and to induce tumor immunity in vivo. This study examined the effects of ultraviolet radiation (UVR) and the cytokines granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and tumor necrosis factor α (TNF‐α) on the ability of epidermal cells (ECs) to induce or to elicit immunity against the murine spindle cell tumor S1509a. Naive syngeneic mice were immunized three times at weekly intervals with ECs that had been cultured in GM‐CSF for 18 h and then pulsed with TAA derived from S1509a. This resulted in protective immunity against subsequent tumor challenge, providing a model to study the conditions required for sensitization against TAAs by epidermal APCs. Culture of ECs in GM‐CSF was required for induction of significant protective tumor immunity, and UV irradiation or incubation in TNF‐α for 2 h after GM‐CSF incubation abrogated the immunostimulatory effect of GM‐CSF. However, unlike UVR, TNF‐α did not significantly inhibit the induction of immunity when ECs were exposed to TNF‐α before overnight incubation in GM‐CSF, together with GM‐CSF, or after pulsing with TAA, and anti‐TNF‐α antibody treatment did not abrogate the effects of UVR on this system. Furthermore, TNF‐α incubation of ECs augmented their ability to elicit delayed‐type hypersensitivity (DTH) and also enhanced elicitation of DTH by GM‐CSF–cultured ECs, whereas UV‐irradiation reduced it in a dose‐dependent fashion. Taken together, these results demonstrate that GM‐CSF, TNF‐α, and UVR are significant regulators of tumor antigen presentation by epidermal APCs and that the effects of the cytokines examined differ with regard to induction or elicitation of immunity.

Molecular cloning of a G protein-coupled receptor that is highly expressed in lymphocytes and proliferative areas of developing brain

A G protein-coupled receptor has been cloned from a sheep pars tuberalis cDNA library using a probe generated by the polymerase chain reaction. The cDNA, designated AJ-13, encodes a protein of 353 amino acids. The structure of the receptor protein encoded by AJ-13 is most similar to that of the interleukin-8 (33-37% identical) and angiotensin II (35% identical) receptors. Examination of the tissue distribution of AJ-13 mRNA by Northern blot analysis and in situ hybridization showed that the transcript is heavily expressed in B and T lymphocytes. In brain, mRNA expression is developmentally regulated, being most highly expressed in proliferative areas. This pattern of expression suggests that the receptor encoded by AJ-13 may have roles in both immune function and brain development.

PRESENTATION OF TUMOR ANTIGENS BY LANGERHANS CELLS AND OTHER DENDRITIC CELLS

It has long been disputed whether human or animal tumors carry immunogenic epitopes on their surface that allow for recognition and destruction of tumor cells by the host’s immune system. Whereas earlier studies concluded that experimentally induced tumors are often immunogenic, while spontaneously arising neoplasms lack antigenic epitopes, it is now generally accepted that many spontaneously arising malignancies also carry immunogenic epitopes on their cell surfaces. In the clinical situation, the immunogenicity of some tumors—especially in the case of melanoma—is evident by their infiltration with leukocytes as well as by the phenomenon of spontaneous partial or complete tumor regression. In vitro, tumor-specific cytotoxic T lymphocyte (CTL) activity and cytokine secretion of T cells after coculture with tumor targets has been shown for human primary and metastatic melanoma, and both CD4+ and CD8+ tumor-infiltrating lymphocytes have been cloned.1,2 Furthermore, the exact peptide sequences of some of these melanoma antigens are known (Table 9.1).3,4 Thus, at least with regard to some cutaneous neoplasms, there is formal proof that they can be immunostimulatory.