Quantitative studies on tissue transplantation immunity. Finally, several prominent immunosuppressive and tolerance strategies used in primates will be reviewed. Animal experimentation has long provided a rational basis for the translation of treatments and techniques from the bench to the bedside. In general, all first-in-human trials require preparative animal experimentation to allow patients to make truly informed decisions about their participation. Properly designed animal studies in relevant species provide the necessary background experience with a novel approach to reasonably anticipate the efficacy or, at the very least, safety of a planned Pafuramidine intervention. As such, they serve as a foundation on which human trials can be ethically designed, particularly in fields such as immunology, in which the complexity of the interactions involved has prevented the development of any sufficiently predictive in vitro model. Although animal models are far superior to in vitro models in projecting the potential of an approach, it must be recognized that they do not mimic clinical transplantation precisely, and thus cannot be expected to forecast the ultimate experience in humans. The mouse model has formed the backbone of medical research and development for many years owing to the relative ease of breeding and genetic manipulation of the animals at a comparatively low cost. For immunology research, the mouse immune system offers sufficient homology for pathway determination and mechanistic studies, and indeed represents the ideal platform for this type of endeavor. In contrast, the large animal models (dog, pig, and primate) are significantly more expensive Pafuramidine and, with the exception of inbred miniature swine (Sachs 1992; Mezrich et al. 2003), exhibit increased genetic diversity, making definitive mechanistic studies much more difficult, if not impossible. However, this complexity makes large animals suited to preclinical studies, in which the addition of often-unanticipated variables allows for the examination of practicality, safety, and generalized efficacy. In general, mice define pathways, and large animal models help establish whether a particular pathways effect is sufficiently robust to emerge as dominant in the midst of the numerous uncontrolled variables typical of heterogeneous human populations. In specific regard to transplantation immunology, mice have several potential drawbacks. Laboratory mice bred in clean environments and studied between 4 and 8 weeks old have a largely na?ve immune system (Blattman et al. 2002), a fact Pafuramidine likely responsible for the success of therapies, including methods of tolerance induction, in mice, FANCB and their subsequent failure when translated to large animals (Kirk 2003; Sachs 2003), or mice exposed to pathogens (Adams et al. 2003). Additionally, mice do not constitutively express class II antigens on vascular endothelium, unlike other large animal models, which may explain the importance of class II matching in the large animals models (Pescovitz et al. 1984; Choo et al. 1997). Furthermore, the efficacy of any regimen may also be dependent on the strain of mice used (Williams et al. 2000). The relative genetic diversity and immunologic experience of large animals helps to avoid many of these shortcomings, and, indeed, experimentation in a large animal model, most frequently primates (for reasons discussed below), has become a de facto requirement before initiation of human being tests in transplantation (Sachs 2003; t Hart et al. 2004). The complexities of the immune response often cause therapies to fail in transition to large animals, or to humans. This is usually owing to one or a few critical variations between species rather than a failure of the concept. Interspecies variations in drug pharmacokinetics may lead to apparent failure of Pafuramidine a regimen that may have been successful if modifications for distribution or rate of metabolism had been regarded as. Furthermore, modern biologic and antibody-based therapies may be profoundly modified by minor variations in molecular structure of the prospective molecule. The immunologic diversity of large animals can lead to significant.
