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Potent immune responses are induced by encounter with cells from a different (allogeneic) individual. The increased number of responding alloreactive T cells can be explained by the cross-reactivity exhibited by T cell receptors (TCR). This cross-reactivity also allows these TCR to bind to syngeneic major histocompatibility complex molecules expressing peptides derived from pathogens or cancer cells. Initial studies showed that CD3+ lymphocytes isolated from newly diagnosed leukemic patients were able to lyse syngeneic leukemic cells after stimulation with allogeneic cells in about half of the patients. These findings raise the possibility that manipulating the alloreactive responses by patient lymphocytes could result in enhanced anti-cancer responses. Further studies utilized a mouse acute myeloid leukemic cell line, C1498, derived from a C57BL/6 mouse. C57BL/6 splenocytes stimulated with allogeneic stimulator cells were shown to be able to lyse allogeneic target cells as well as the syngeneic C1498 leukemic cells. The level of lysis of the syngeneic leukemic cells was dependent on the strain from which the allogeneic stimulator cells were obtained. Immunization of C57BL/6 mice with C1498 cells or subcellular antigen enhanced the anti-C1498 response when stimulated with allogeneic cells. Ongoing experiments are defining whether naïve or memory effector cells are responsible for the lysis of the syngeneic leukemic cells as well as the nature of the peptide antigens that allow the syngeneic cancer cells to be recognized. The results of these studies will facilitate the use of protocols which harness alloreactive responses by patient lymphocytes to generate anti-cancer responses.

The emerging heterogeneity of dendritic cells (DCs) mirrors their increasingly recognized division of labor at myriad control points in innate and acquired cellular immunity. We separately generated blood monocyte-derived DCs (moDCs), as well as Langerhans cells (LCs) and dermal-interstitial DCs (DDC-IDCs) from CD34+ hematopoietic progenitor cells. Differential expression of CD11b, CD52, CD91, and the CD1 isoforms proved useful in distinguishing these three DC types. All mature DCs uniformly expressed comparable levels of HLA-DR, CD83, CD80, and CD86, and were potent stimulators of allogeneic T cells after exposure either to recombinant human CD40L trimer or a combination of inflammatory cytokines with PGE2. moDCs, however, required 0.5–1 log greater numbers than LCs or DDC-IDCs to stimulate comparable T cell proliferation. Only moDCs secreted the bioactive heterodimer IL-12p70, and moDCs phagocytosed significantly more dying tumor cells than did either LCs or DDC-IDCs. LCs nevertheless proved superior to moDCs and DDC-IDCs in stimulating CTL against a recall viral Ag by presenting passively loaded peptide or against tumor Ag by cross-priming autologous CD8+ T cells. LCs also secreted significantly more IL-15 than did either moDCs or DDC-IDCs, which is especially important to the generation of CTL. These findings merit further comparisons in clinical trials designed to determine the physiologic relevance of these distinctions in activity between LCs and other DCs.