**4. Dendritic cells – The most potent antigen presenting cells**

Dendritic cells (DCs) are derived from CD34+ progenitor cells in the bone marrow, but otherwise constitute a heterogeneous cell type that is widely distributed in different tissues, including skin, mucosa, lymph nodes and spleen.

Resident DCs in the epidermis (Langerhans cells) and interstitial DCs found in other tissues [7] are believed to be derived from CD14+ myeloid precursor cells (Figure 2).

Recent studies in mice, however, have suggested that both subsets can be derived from fmsrelated tyrosine kinase 3 (Flt3)-expressing myeloid and lymphoid progenitors, and that plasmacytoid DCs may differentiate into myeloid DCs following viral infection.

Dendritic cells are considered to be the most potent antigen presenting cells and are instru‐ mental in eliciting immune responses. DCs capture antigen in the tissues and then migrate to regional lymph nodes where they encounter T cells in the paracortal area.

Most DCs in the skin and other tissues have an immature phenotype. These cells are effective at engulfing antigen and constantly sample their environment, but have a limited ability to migrate and to stimulate T cells. If immature DCs reach the lymph nodes and present antigens to T cells, they are likely to induce anergy rather than activation, due to their low expression of co-stimulatory molecules. In the non-inflammatory setting, the immature DCs thus promote immunological tolerance by capturing and presenting endogenous antigens. Mature DCs, however, are potent inducers of immunity.

Maturation of DCs is commonly induced by inflammatory cytokines or by the capture of microbial ligands that stimulate Toll-like receptors (TLRs).

**Figure 2.** Subsets of dendritic cells (DCs). All DC-subsets are derived from CD34+ haematopoietic profnitor cells in the bone marrow. Interstitial DCs and Langerhans cells are believed to be of myeloid origin. The plasmacytoid DCs are traditionally considered to be of lymphoid origin.

Contrary to immature DCs, the mature cells rapidly migrate to regional lymph nodes, as has been demonstrated in vivo in melanoma patients by Devries and his research group [7].

Moreover, mature DCs strongly up-regulate their expression of HLA class II and co-stimula‐ tory molecules, and are highly effective at activating naïve CD4+.

DCs also present engulfed antigens on HLA class I and may thus directly stimulate CD8+ T cells.

Finally, the phenotype of mature DCs, including their cytokine secretion pattern, is believed to direct the differentiation of CD4+ T cells into Th1- or Th2-type cells.

#### **5. Tumour-associated antigens**

Th1-cytokines, while the Th2-cytokines include IL-4, IL-5, IL-6, IL-10 and IL-13.

In cancer immunotherapy, Th1-type responses are generally believed to be desirable.

differentiation, while Th2-cytokines have the opposite effects [5, 7].

**4. Dendritic cells – The most potent antigen presenting cells**

[7] are believed to be derived from CD14+ myeloid precursor cells (Figure 2).

plasmacytoid DCs may differentiate into myeloid DCs following viral infection.

regional lymph nodes where they encounter T cells in the paracortal area.

including skin, mucosa, lymph nodes and spleen.

however, are potent inducers of immunity.

microbial ligands that stimulate Toll-like receptors (TLRs).

responses by interaction with B cells.

8 Immunopathology and Immunomodulation

be our next publication [8].

Th1 cells support cellular immunity, e.g. by secreting cytokines that induce up-regulation of HLA on target cells and stimulate macrophages and CD8+ T cells. Th2 cells promote antibody

Antibody responses can only target surface antigens, whereas the CD8+ T cells are able to recognize intracellular antigens presented on HLA class I. Th1- and Th2-responses are mutually inhibitory. Th1-cytokines generally promote Th1-differentiation and inhibit Th2-

Th2-cytokines may therefore suppress the development of cytotoxic anti-tumour responses.

There are considerable experimental data on the effects of individual Th1- or Th2-cytokines.

However, the validity of the Th1/Th2-delineation in humans may be questioned, which could

Dendritic cells (DCs) are derived from CD34+ progenitor cells in the bone marrow, but otherwise constitute a heterogeneous cell type that is widely distributed in different tissues,

Resident DCs in the epidermis (Langerhans cells) and interstitial DCs found in other tissues

Recent studies in mice, however, have suggested that both subsets can be derived from fmsrelated tyrosine kinase 3 (Flt3)-expressing myeloid and lymphoid progenitors, and that

Dendritic cells are considered to be the most potent antigen presenting cells and are instru‐ mental in eliciting immune responses. DCs capture antigen in the tissues and then migrate to

Most DCs in the skin and other tissues have an immature phenotype. These cells are effective at engulfing antigen and constantly sample their environment, but have a limited ability to migrate and to stimulate T cells. If immature DCs reach the lymph nodes and present antigens to T cells, they are likely to induce anergy rather than activation, due to their low expression of co-stimulatory molecules. In the non-inflammatory setting, the immature DCs thus promote immunological tolerance by capturing and presenting endogenous antigens. Mature DCs,

Maturation of DCs is commonly induced by inflammatory cytokines or by the capture of

The tumour-associated antigens comprise tumour-specific antigens, overexpressed antigens, cancer-germline antigens, viral antigens and tissue-differentiation antigens. Antigens which are virtually tumour-specific may arise from genomic mutations, e.g. K-RAS or post-transla‐ tional modifications, e.g. MUC-1. Other antigens used in cancer vaccines, like hTERT, survivin, and HER2/neu, are widely expressed in normal tissues, but overexpressed in tumour cells.

In contrast, the expression of cancer-germline antigens, e.g. the melanoma antigens MAGE-1 and MAGE-3, is restricted to tumour cells and normal germline cells (testis and placenta).

Viral antigens represent attractive vaccine targets for virus-induced cancers and are included in the prophylactic vaccines mentioned above for cervical carcinoma (Human papilloma virus) and hepatocellular carcinoma (Hepatitis B virus).

The differentiation antigens are tissue-specific, i.e. expressed only in normal and neoplastic cells from a particular lineage. These antigens may be utilized in cancer vaccines if an auto‐ immune reaction to the relevant tissue is tolerable.

For instance, prostatitis or vitiligo may represent acceptable adverse effects for patients with prostate cancer or malignant melanoma, respectively.

Several differentiation antigens are extensively used in cancer vaccines, including prostatespecific antigen (PSA) and the melanoma antigens Melan a/Mart-1, gp100 and tyrosinase [6, 7, 8].
