Physiological Incompatibilities Research Articles

A reversibly immortalized human hepatocyte cell line as a source of hepatocyte‐based biological support

The application of hepatocyte transplantation (HTX) is increasingly envisioned for temporary metabolic support during acute liver failure and provision of specific liver functions in inherited liver-based metabolic diseases. Compared with whole liver transplantation, HTX is a technically simple procedure and hepatocytes can be cryopreserved for future use. A major limitation of this form of therapy in humans is the worldwide shortage of human livers for isolating an adequate number of transplantable human hepatocyes when needed. Furthermore, the numbers of donor livers available for hepatocyte isolation is limited by competition for their use in whole organ transplantation. Considering the cost of hepatocyte isolation and the need for immediate preparation of consistent and functional cells, it is unlikely that human hepatocytes can be obtained on such a scale to treat a large number of patients with falling liver functions. The utilization of xenogenic hepatocytes will result in additional concerns regarding transmission of infectious pathogens and immunological and physiological incompatibilities between animals and humans. An attractive alternative to primary human hepatocytes is the use of tightly regulated human hepatocyte cell lines. Such cell lines can provide the advantages of unlimited availability, sterility and uniformity. We describe here methods for creating transplantable human hepatocyte cell lines using currently available cell cultures and gene transfer technology.

Prospective of human butyrylcholinesterase as a detoxifying antidote and potential regulator of controlled-release drugs

Butyrylcholinesterase from human plasma (HuBChE) is a potential drug candidate that can be employed in several therapeutic fields. This is attributed to the unique structure of the enzyme that allows selective accommodation of a variety of substrates and inhibitors, some of which are excluded from the catalytic gorge of acetylcholinesterase. Enhancement of endogenous levels of HuBChE can protect against the toxicity of organophosphate pesticides and nerve agents, reduce risks of complications due to cocaine abuse, reverse muscle relaxant-induced apnea following surgery anesthesia, and alleviate symptoms caused by local anesthetics. It can be used either prophylactically or as a treatment drug. Treatment with HuBChE offers replacement therapy of traditional pharmacological antidotes that suffer from several disadvantages. In addition, endogenous HuBChE is capable of biotransformation of ester- or carbamate-bond containing prodrugs to active therapeutic molecules, and has the potential of improvement of bioavailability and safety of numerous drugs with sales records. In certain cases HuBChE may be administered before, with, or after the prodrug. HuBChE is absorbed in high yield from muscles and its circulatory stability is sufficient to provide significant therapeutic levels for several days, even after a single dose load. Based on limited studies with partially purified HuBChE, the enzyme seems to lack significant physiological incompatibilities in humans that may prevent its use as a drug. Clinical trials aimed at providing pharmacokinetic data and evaluation of safety issues of acute and chronic administration of purified HuBChE are expected to advance the concept of using the enzyme as a multipurpose drug. Drug Dev. Res. 50:298–308, 2000. © 2000 Wiley-Liss, Inc.

Physiologic incompatibilities in discordant xenotransplantation

At present, several incompatibilities between pig and human, not only from the immunologic point of view but also regarding physiological and molecular systems, have been identified. It is anticipated that this is only the tip of the iceberg regarding this topic. However, there are also many systems that are compatible. Strategies have been outlined, and many tools, such as gene modification, are available to solve the problems. Therefore, the statement by Keith Reemtsma in the foreward to the latest issue of the monography Xenotransplantation "The important question is not whether xenotransplantation will succeed, but rather how and under what circumstances xenografts will provide predictable enough results to warrent clinical application" will hopefully be a reality in the future.

STUDIES OF LYTHRUM SALICARIA I. THE EFFICIENCY OF SELF‐POLLINATION

The conditions that exist in species with trimorphic flowers permit the investigation of the problems regarding the nature of sex-differentiation and the degrees of compatibility between male and female organs under very favorable circumstances. In these forms the morphological adaptations for cross-pollination are often decidedly correlated with physiological incompatibilities which make cross-fertilization more certain by excluding the functioning of the chance self-pollinations which occur. In general it is to be recognized that sexual fusions are favored by similarity of the gametes both in genetic constitution and in immediate origin, and that such conditions as trimorphism and self-incompatibility are to be regarded as, in a high degree, secondary and acquired. While these conditions secure the advantages of bringing together gametes of different origins and in greater or less degree of different genetic constitution, they decidedly limit and restrict free fertilization and full productivity. The combination of morphological trimorphism with physiological incompatibilities as seen in species like Lythrum Salicaria may well be regarded as the highest degree of specialization in sex-determination and fertilization that exists in flowering plants. For this species there is the obvious morphological differentiation giving three lengths of pistils and three sets of stamens of lengths corresponding to those of the pistils, with the stamens bearing pollen differentiated as to size, color, and nature of the reserve food material in storage. For the individual, the flower of any particular plant has a pistil of one of the three lengths and a set of stamens for each of the other two lengths. This gives differentiation of forms as such, and in the single plant there is the differentiation that gives two kinds of stamens. Furthermore, this morphological differentiation is decidedly correlated with physiological differentiation. The noteworthy researches of Darwin (I865, I877) showed that there is marked or even complete sterility to (i) selfpollinations, to (2) intra-form cross-pollinations, and to (3) the interform cross-pollinations that are illegitimate (i.e., those that involve different lengths of pistil and stamen). Seed-production was hence found to be more or less limited to legitimate pollinations, which are necessarily crosses. The specializations in these forms allow no doubts as to their significance such as have often been raised in regard to the colors of entomophilous flowers, for here the adaptations are morphological and depend directly