Abdominal aortic aneurysm is a specific antigen-driven T cell disease.

To determine whether monoclonal/oligoclonal T cells are present in abdominal aortic aneurysm (AAA) lesions, we amplified beta-chain T cell receptor (TCR) transcripts from these lesions by the nonpalindromic adaptor (NPA)-polymerase chain reaction (PCR)/V-beta-specific PCR followed by cloning and sequencing. Sequence analysis revealed the presence of substantial proportions of identical beta-chain TCR transcripts in AAA lesions in 9 of 10 patients examined, strongly suggesting the presence of oligoclonal populations of alphabeta TCR+ T cells. We have also shown the presence of oligoclonal populations of gammadelta TCR+ T cells in AAA lesions. Sequence analysis after appropriate PCR amplification and cloning revealed the presence of substantial proportions of identical VgammaI and VgammaII TCR transcripts in 15 of 15 patients examined, and of Vdelta1 and Vdelta2 TCR transcripts in 12 of 12 patients. These clonal expansions were very strong. All these clonal expansions were statistically significant by the binomial distribution. In other studies, we determined that mononuclear cells infiltrating AAA lesions express early- (CD69), intermediate- (CD25, CD38), and late- (CD45RO, HLA class II) activation antigens. These findings suggest that active ongoing inflammation is present in the aortic wall of patients with AAA. These results demonstrate that oligoclonal alphabeta TCR+ and gammadelta TCR+T cells are present in AAA lesions. These oligoclonal T cells have been clonally expanded in vivo in response to yet unidentified antigens. Although the antigenic specificity of these T cells remains to be determined, these T cells may play a significant role in the initiation and/or the propagation of the AAA. It appears that AAA is a specific antigen-driven T cell disease.

Substantial proportions of identical beta-chain T-cell receptor transcripts are present in epithelial ovarian carcinoma tumors.

To determine whether clonally expanded T cells are present in tumor specimens from patients with epithelial ovarian carcinoma (EOC) we amplified by the non-palindromic adaptor PCR (NPA-PCR) or by Vbeta-specific PCR beta-chain T-cell receptor (TCR) transcripts from these tumor specimens. The amplified transcripts were cloned and sequenced. Sequence analysis revealed the presence of substantial proportions of multiple identical copies of beta-chain TCR transcripts, suggesting the presence of clonal expansions of T cells in these patients, which were statistically significant by the binomial distribution in seven of nine patients. Independent amplification in separate experiments of beta-chain TCR transcripts from one patient by either NPA-PCR or by Vbeta-specific PCR, followed by cloning and sequencing, revealed identical clonal expansions irrespectively of the amplification method used. Multiple identical copies of beta-chain TCR transcripts can be derived only by specific antigen-driven proliferation and clonal expansion of the T-cell clones which recognize these antigens. Because of the very large size of the TCR repertoire, the probability of finding by chance multiple identical copies of these transcripts within an independent sample of T cells is negligible. These results demonstrate that T cells infiltrating solid tumor specimens or malignant ascites of patients with EOC contain monoclonal/oligoclonal populations of T cells.

Immune responses to human tumors: development of tumor vaccines.

Strong evidence has been accumulated demonstrating that tumor cells in humans and animal are recognized in general as non-self by the immune system and they are able to induce an immune response which often leads to their elimination. In humans, this evidence includes: (a) The development of T-cell lines and clones with antitumor activity (cytotoxic or helper) which is restricted to autologous tumor cells or to cells expressing the same tumor peptide/HLA epitope; (b) the presence of oligoclonal T cells infiltrating many tumors; (c) the identification and molecular cloning of tumor antigens and of peptides derived from these antigens, which elicit HLA-restricted immune responses. Their discovery provided the ultimate proof for the presence of specific immune responses in human tumors. The availability for the first time of molecularly cloned tumor antigens permitted the development of peptide or recombinant tumor vaccines. Although significant progress has been made and tumor peptide vaccines capable of eliciting biological responses in more than 50% of the patients and objective clinical responses in 10 to 42% of the patients have been reported, certain major problems remain and need to be resolved in order to develop effective tumor vaccines. These problems emanate from the following mechanisms that the tumor cells are employing to avoid detection and destruction by the immune system: (i) Down-regulation of HLA class I expression on the surface of tumor cells; (ii) Down-regulation of tumor antigen expression or selection of negative tumor variants; (iii) Expression of naturally occurring altered peptide ligands by tumor cells; (iv) Lack of costimulatory molecules on tumors cells; (v) Production of immunosuppressive cytokines, such as TGF-beta and IL-10; (vi) Induction of lymphocyte apoptosis by tumor cells using the Fas/Fas L pathway; (vii) Down-regulation or absence of CD3 zeta (zeta) transcripts or protein in tumor-infiltrating lymphocytes (TIL), and others. The selection of optimal tumor antigens for vaccine development is another issue that requires attention. Lineage specific or differentiation antigens appear to be better candidates for the development of tumor vaccines because they are expressed in all tumor cells. Methods for antigen presentation, such as those using dendritic cells, also play a critical role in the development of tumor vaccines. In addition to the progress towards the development of tumor vaccines, substantial progress has been made in developing advanced methods of adoptive immunotherapy based on TIL. This approach can be effective when an immune response can not be elicited in vivo. The progress made towards the development of tumor vaccines and approaches for adoptive immunotherapy has been substantial. Additional studies need to be carried out to develop new and effective tumor vaccines and adoptive immunotherapy methods.