The complexity of immune and alloimmune response.

Alloimmune response induced by foreign histoincompatible alloantigens is a complex phenomenon possessing mechanisms, characteristics to innate and adoptive immune response. It is also modified by various immunregulating exocrine and autocrine factors. Starting the new time period of functional genomics the knowledge of human genes' structure needs a more clear insight not only about the function and contribution of genes but their historical background, origin and importance in the phylogenesis. Comparative immunology comes into focus of interest helping to understand the complexity of immune and alloimmune response. It is almost unbelievable that immune functions as phagocytosis and cytokine production like IL-1 and TNF have already emerged 700 million years ago in starfishes and sponges. Functions--including recruitment of coelomocytes, killing of micro-organisms by lysosome-like enzyme activity, opsonization by complement analogous proteins and oxidative burst function--remained unchanged during phylogenesis and could be found not only in insects but in mammals as well as representatives of innate immunity. The importance of these molecules is reflected in homology of conservative regions. One of the biggest evolutionary steps happened 500 million years ago when fish developed a jaw in the Placoderms species. This fact led to the development of gut associated immune system. The system was the basis to create the genetic material for recombination and mutation to establish variability and diversity of proteins, as immunoglobulins. It is interesting to lean how diversity of immunglobulins in sharks is insured by joining of blocks of V, D, J and C genes, in contrast to humans, where those genes are located on different chromosome regions. These differences are associated with an immediate production of specific immunglobulin or a slower one combined with immunologic memory. Similar development could be found in T cell antigen specific receptors, too. Concerning the establishment of adoptive immunity by emergence of genetic recombination, which allowed the production of a huge diversity of specific antigen binding proteins, another structure developed parallel from the histoglobin molecule. This protein was created to catch peptide particles which split from the proteins originating from microorganisms, viruses or foreign cell compartments. The cave-like groove capturing the different peptides represented a huge variability. These histocompatibility molecules emerged from this ancient structure for more than 300 million years ago. The genetic family responsible for their synthesis became the most complex gene family including many other genes involved in the immune response. The polymorphic character of the histocompatibility protein is responsible for the capture of the relevant peptides fitting best to the allotype-determined groove. In certain species the same function could be filled by different ancient molecules with the same success. Dendritic cells and their importance in differentiation and antigen presentation became in the focus of interest in the last decade. They have lymphoid and myeloid origin, mature and less differentiated subtypes with characteristic CD markers and cytokine profile. Their function and origin from the stem cell subpopulation is an important example how nature influences the development of immunity to the accommodation and survival to the always changing environment. The new molecular techniques will help to get closer to understand the function of genes regulating immune response and modify them.

The pattern of cytokine gene expression in human colorectal carcinoma.

Systemic and local cytokine environment may modulate the immunogenicity of colorectal cancer cells, and affect anti-tumor immune functions of tumor-infiltrating lymphocytes. We therefore investigated cytokine mRNA expression patterns in tumors and peripheral blood mononuclear cells (PBMC) from patients with colorectal adenocarcinoma. IL-2, IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), IL-4, IL-6, IL-8, IL-10 and IL-1 beta mRNAs in single cell suspension of freshly isolated colorectal cancer tissue were studied by RT-PCR. Frequencies of cytokine gene expression were compared to those in normal colonic mucosa from tumor patients. The frequencies of IL-2, IFN-gamma, IL-4 and IL-10 gene expression were also determined in peripheral blood mononuclear cells from patients with colorectal adenocarcinoma and compared to those of healthy individuals. Tumor samples were more frequently positive for IFN-gamma, IL-2, TNF-alpha and IL-10 gene expression than normal mucosa (p=0.0001, p=0.0118, p=0.001 and p<0.0001, respectively). Frequencies of IL-2 and TNF-alpha gene expressions were significantly higher in tumors with a diameter <5 cm, than in those with a diameter >5 cm. The genes for IL-6, IL-1 beta and IL-8 were commonly expressed in both tumor tissue and normal colonic mucosa. IFN-gamma transcripts were detected in more PBMC samples from patients with colorectal cancer than those from normal controls (p=0.0449). Thus, colorectal cancer tissue is characterized by a specific pattern of cytokine gene expression. It is likely that multiple interactions between pro- and anti-inflammatory cytokines regulate tumor growth and the functional activity of tumor-infiltrating lymphocytes.

The induction of active or peripheral tolerance in organ transplantation: dream or reality.

Immunological tolerance induction is one of the most exciting research fields in experimental and clinical transplantation. From the first discovery of Nobel Prize awarded to L. Brent and P. Medawar, beside the classical induction of central tolerance in newborn mice, several methods, interventions and compounds have been introduced with a view to establishing tolerance. It was clarified that the mechanisms have different characteristics for central and peripheral or active/operative transplantation tolerance. In the case of the latter, tolerance was accompanied with mixed chimeric state. In the last decade, new compounds, such as monoclonal antibodies specific for membrane receptors on T- and APC cells responsible for signal 1 and signal 2 functions have been employed to induce operative tolerance. Among various methods and immunosuppressive interventions, non-myeloablative treatments combined with hematopoietic stem cell infusion showed the most effective results. This form of induction is associated with the well known "beneficial transfusion effect" in kidney transplantation. Based on the experimental achievements of clinical organ transplantation, various protocols have been introduced to induce peripheral tolerance. In spite of the short observation time of this progress the results seem to be promising, first of all, in the prolonged rejection-free survival time of the graft and the possibility to withdraw the immunosuppressive treatment altogether.