Kidney and spleen twin grafts in rats: unidirectional graft acceptance in unsuppressed ACI recipients.

In previous studies, we have shown that vascularized spleen grafts can facilitate the acceptance of simultaneously implanted hearts, especially if host splenectomy is done 3 days later. The present study shows that the same protocol works not only for hearts but also for kidneys. A total of 59 renal allografts were carried out in various combinations between LEW and ACI rats. The recipients were submitted to bilateral nephrectomy at the time of graft implantation and host splenectomy 3 days later. Graft function was assessed by survival time of the animals. In addition, BUN, creatinine, and hematocrit were measured in selected individuals. The following observations were made: 1) LEW kidneys were rejected at 92 +/- 65 days while ACI kidneys failed at 17 +/- 1.4 days (p less than 0.025). 2) Control animals without simultaneous syngenic functioning spleen implant rejected their LEW kidneys at 30.6 +/- 24.3 days (p less than 0.005). 3) Eleven rats never rejected their LEW kidneys (four single, seven twin grafts). 4) BUN, creatinine, and hematocrit differed significantly in rats with functioning kidneys compared to those in end stage renal failure (p less than 0.0005, p less than 0.0025, and p less than 10(-7) respectively). It is concluded that the presence of the donor spleen can facilitate the acceptance of a simultaneous kidney graft to various degrees, depending on the strain combination.

Glycerokinase activity in human adipose tissue as related to obesity.

The activity of the enzyme glycerokinase is low in mammalian adipose tissue, but high in certain forms of genetic obesity in rats and mice. This study was undertaken to determine if obese human subjects had higher glycerokinase activity than normal-weight subjects. Seventy-three randomly selected patients undergoing abdominal surgery were studied. Subcutaneous and omental adipose tissue was removed during surgery and the activity of the enzyme glycerokinase was measured in vitro under optimal conditions. The following observations were made: (1) the mean activity, when expressed per microgram DNA, was significantly (P less than 0.05) higher in obese subjects at both sites, yet no direct correlation to the degree of obesity was found; (2) the individual activity in morbidly obese patients undergoing gastroplasty correlated inversely with the rate of postoperative weight loss (r = -0.58, P less than 0.05); (3) glycerokinase activity was directly related (r = 0.59, P less than 0.01) to the rate of spontaneous glycerol release, and inversely related (r = -0.51, P less than .025) to the stimulation in glycerol release by norepinephrine; (4) the ratio glycerokinase/lipoprotein lipase in omental adipose tissue correlated with the degree of obesity (r = 0.43, P less than 0.05); (5) in nondiabetic male obese adults, the glycerokinase activity in subcutaneous adipose tissue inversely correlated with age (P = 0.05) and (6) the glycerokinase activity had two apparent Km values in three obese patients, in which it was studied kinetically. It is concluded that a small subsection of the obese population have a high potential for glycerol phosphorylation. In these individuals, weight loss is more difficult since they tend to reutilize the glycerol formed by lipolysis and net glycerokinase activity in their adipose tissue may reflect variations in lipid turnover.

Heart and spleen "twin grafts" in rats: morphology and function in permanent survivals.

A new rat allograft model has been investigated for its potential to facilitate organ transplantation. In this procedure heart and spleen of male inbred LEW rat (RT1') were connected to the main abdominal vessels in inbred ACI rat (RT1a). With optimal surgical technique we obtain 64% permanent graft survival (5-14 months) in the splenectomized recipients. Cardiac histology ranged from preserved myocardium with moderate thickening of coronary artery walls to diffuse myocardial fibrosis with marked involutional changes of coronary arteries. Whereas palpation and EKG wrongly indicate good function beyond the fourth month, only the phonocardiogram shows the rapid functional loss which reflects the true morphologic involution.

Heart and spleen "twin grafts" in rats: IV. Influence of donor spleen cell mass on allograft survival.

Heart and spleen twin grafts from LEW to ACI rats may survive permanently, whereas those grafted from ACI to LEW rats do not. This strain difference in graft acceptance was analyzed quantitatively by transplanting one to three ACI spleens into LEW rats in order to compensate for the relatively small size of ACI spleens (Fig. 1). Under these conditions permanent graft survival was not observed in LEW recipients. However, during host splenectomy 3 days after transplantation, a nonimmunological factor was observed. The transplanted ACI spleens showed congestion and infarctions, while in the LEW to ACI transplant model the LEW spleens did not. This observation could be explained by the size of the vascular pedicle in ACI spleens. Although no problem was encountered immediately after completing the anastomoses, allogeneic spleens react by increasing in size, to such an extent that their size exceeds the capacity of the smaller vascular pedicle in ACI rats and results in congestion. Hence, the concept is formulated that early compromise of hemodynamics on a nonimmunological base may determine the fate of ACI spleen graft before immunological factors have a chance to become effective.

Emergency transumbilical embolization of bleeding esophageal varices.

Eight patients had major hemorrhage from esophageal varices; in seven, one or two embolizations of the coronary and short gastric veins resulted in cessation of hemorrhage. This procedure can be used in patients with massive ascites, severe coagulopathy, or profound liver failure, as the access route through the dilated umbilical vein can be reached via a supraumbilical incision done with the patient under local anesthesia. All patients died; two deaths were attributable to complications of the procedure, the other six to the severity of the cirrhosis. Sclerotherapy may be combined with coronary vein embolization, but the risk of esophageal perforation may be greater than with sclerotherapy alone.

Heart and spleen twin grafts in rats. II. Delayed host splenectomy.

Simultaneous auxiliary transplantation of the spleen has been shown to delay and attenuate the rejection of cardiac grafts in rats. In the experiments reported here, 144 such twin grafts in Lewis and ACI rats were explored in an attempt to determine whether removal of the host's spleen would further facilitate graft survival in this model. Thus, 87 rats were submitted to host splenectomy at various time intervals after implantation of the twin grafts. After considerable technical problems were overcome, it was found that this additional maneuver induced permanent (greater than 5 months) survival in 64% of Lewis-to-ACI twin grafts. The important requirement for this success was timing; delaying host splenectomy for 3 to 5 days after implantation of the twin graft was mandatory.

Heart and spleen twin grafts in rats.

The technical details of a new procedure for the simultaneous transplantation of the spleen and the heart in rats are described. One hundred sixty-four such twin grafts from LEW to ACI rats and vice versa were performed. Seventeen animals were followed postoperatively without additional immunologic manipulations. There is a definite change in rejection pattern in terms of timing as well as intensity when heart and spleen twin grafts are compared with single cardiac grafts. A delay and mild form of rejection of twin grafts were observed especially in the strain combination of LEW to ACI. No graft-versus-host reaction occurred. There was no perfect correlation of the cardiac and splenic allografts in regard to their survival time. When the cardiac allograft arrested, however, the spleen was found to be rejected as well in all cases. In three cases a selective survival of the heart over the spleen was observed. Thus, the cardiac allograft can be used as a simple but not completely reliable indicator of the functional state of both grafts.

Phonocardiographic recording of heterotopic cardiac graft function in the rat. I. Diagnosis of rejection.

Daily simultaneous recordings of an electrocardiogram and an external thorax phonocardiogram and abdominal phonocardiogram were obtained in 24 rats with abdominal heart grafts so that rejection could be studied. The sounds recorded above the heterotopic heart are the result of a pressure differential between host and graft ventricle competing with one another. As soon as the contractility of the graft ventricle decreases below the contractility of the host ventricle, characteristic and specific changes occur in the abdominal phonocardiogram: the amplitude of the first sound becomes smaller while the timing of the second heart sound (aortic valve closure) is subsequently controlled by the host ventricle. These observations coincide with clinical and histological symptoms of rejection and are, therefore, of diagnostic value. In addition, a rough quantitative record of graft function is obtained by abdominal phonocardiography using the host's own cardiac function as a reference parameter.

[Transplantation antigens: the individual in biology and psychology]. / Transplantationsantigene: Das Individuum in der Biologie und Psychologie

The persistent defense of biological individuality is explained on the basis of the concept that "foreign" and "self" are complementary phenomena. Since it is the T-lymphocyte of the immune system which recognizes "foreign", its receptor must represent "self". How is this accomplished in immunogenetic terms? An intriguing possibility would be the somatic reduplication and amplification of "self" through random combinatorial principles by means of exclusion: all receptors are formed, but those directed against "self" suppressed while the others (including those identical with "self") remain at disposition. In this way, HLA gene products, rather than representing immune receptors themselves, would prime the formation of the immunological repertoire indirectly. The concept that "self" plays the role of a template copied by the actual recognition system is supported by elementary information theory. Analogies to other, higher biological information systems such as the brain are drawn. Moreover, since neuroscience and psychology are in fact inseparable, the analogies reach even much further. A common blueprint can be traced from primitive cell to cell interactions through molecular immunology to neurochemistry, psychology and philosophy. Particularly Jung's concept of psychological individuation as the never-ending struggle of the human individual for consciousness would precisely fit the role of "molecular individuation" as a means of acquiring the immunological repertoire. In psychological terms "foreign" corresponds not only to the outer world (antigens( but also to our own unconscious (antiidiotypic set) resulting in a similar network of mutual interactions between conscious and unconscious much as between idiotypes and anti-idiotypes.

"Self": standard of comparison for immunological recognition of foreignness.

It is suggested that the markers of biological individuality--i.e. the HLA antigens--may serve as the standard profiles against which foreignness is directly compared.

Nonspecific complement activation by streptococcal structures. I. Re-evaluation of HLA cytotoxicity inhibition.

A number of experiments have suggested that there is an antigenic relationship between the HLA complex and streptococcal bacterial structures. Using inhibition of cytotoxicity of HLA antisera as our assay system, it was demonstrated that the inhibitory effect on HLA cytotoxicity by streptococcal antigens is, in reality, due to activation and consumption of components of the alternate complement pathway. In addition, antisera prepared against streptococcal membrane antigens had no cytotoxic effect on a large panel of human lymphocytes, nor did these antisera exhibit immunofluorescent staining of lymphocytes directly. These experiments are compatible with our concept that the HLA complex may have evolved through selective evolutionary pressure as a means of escaping bacterial mimicry.

Nonspecific complement activation by streptococcal structures. II. Properdin-independent initiation of the alternate pathway.

Complement consumption by isolated membranes and walls from Group A streptococci and various other gram-positive microbes has been tested. These microbial structures were found to activate the alternate complement pathway. However, unlike endotoxin, inulin, or other plant polysaccharides, activation of complement by our material was found to bypass properdin. The activating factor(s) also differs from cobra venom in its/their requirement for factor D. Preliminary experiments suggest this factor isolated from membranes to be a protein and to have a mol wt greater than 40-60,000 daltons. Our studies have led us to speculate that the phylogenetic role of the alternate complement pathway may be the primordial nonspecific defense system which has retained certain fundamental aspects up to the present time.