IMMUNE MECHANISMS IN PARABIOSIS INTOXICATION

When A strain mice are placed in parabiotic union with (A x C57Bl/1)F1 hybrid partners, the parental strain partners are polycythemic and the hybrids anemic from the 5th through the 16th parabiosis days. All hybrids develop clinical intoxication between the 7th and the 12th days, and no pairs survive to 1 month. Long-term survival of parabiotic pairs can be achieved if lethally irradiated or specifically tolerant parental strain mice are united to hybrid partners. Production of tolerance by either of these methods results in elimination of anemia-polycythemia by the 12th parabiosis day and prevents intoxication in the hybrid partners. Preimmunization of the parental strain partners against the C57Bl/1 component of the hybrid leads to a considerable intensification of day 5 anemia-polycythemia. Intoxication develops in the hybrid partners between the 4th and the 6th days after union. It is concluded that anemia is primarily responsible for the syndrome of clinical intoxication. Early anemia-polycythemia on day 5 does not depend upon an immunological mechanism, but the late anemia-polycythemia appearing between days 12 and 16 is a function of the ability of the parental strain mouse to react immunologically against its hybrid partner. When neonatally thymectomized A strain mice are joined to hybrid partners, anemia-polycythemia is sustained through the 16th day and the hybrid partners develop clinical intoxication. On the other hand, when both partners are neonatally thymectomized, late anemia-polycythemia is considerably reduced, and the hybrid partners apparently do not develop clinical intoxication. It is concluded that normal hybrid mice are capable of reconstituting the immunological capacity of their thymectomized partners, whereas thymectomized hybrid mice do not have this restorative capacity. These findings are discussed in terms of their possible application to the problem of the induction of immunological tolerance in adult mice by the parabiosis procedure

THE ROLE OF THE THYMUS IN DEVELOPMENT OF IMMUNOLOGIC CAPACITY IN RABBITS AND MICE

In rabbits, complete thymectomy before the age of 5 days produced immunologic deficiency in the adult animals, as indicated by reduced antibody production to bovine serum albumin and bacteriophage T2. Homotransplantation immunity was unaffected, however. In an inbred strain of mice, complete neonatal thymectomy resulted in complete inability of the 60-day-old animals to form antibody to bacteriophage T2. Inbred mice, completely thymectomized at birth, had a deficient homograft response, indicated by acceptance of skin homografts from strains differing in both the weaker and stronger (H-2) histocompatibility antigens. Tumor transplants (mammary adenocarcinoma) were also successful across the H-2 genetic barrier in mice thymectomized at birth. Neonatal thymectomy also eliminated the Eichwald-Silmser phenomenon, rendering female mice capable of accepting isografts of male skin. Transplantation immunity in mice was also affected by later thymectomy, at 30 days of age, in certain strain combinations involving weak histocompatibility differences. Spleen and lymph node cells from mice thymectomized at birth or at 6 days of age, and sacrificed 2 months later, did not produce a graft versus host reaction in appropriate F1 hybrid recipients, indicating that such cells are immunologically inactive. Neonatal thymectomy of F1 hybrid mice, and in one strain combination thymectomy at 40 days of age, produced animals with inordinate susceptibility to runt disease (homologous disease) following injection of parent strain spleen cells 35 days (neonatal surgery) and 10 days (surgery at 40 days) later. Mice thymectomized at birth also showed growth failure and were short-lived. Studies of newborn mice indicated that they have true lymphocytes only in the thymus, and lack such cells in the spleen, lymph nodes, and gut. In normal mice, adult lymphoid structure develops gradually, beginning during the 1st week of life and continuing for the next month. In contrast, mice thymectomized at birth do not develop mature lymphoid structure: the lymph nodes and spleens tend to be small and poorly organized, and show a quantitative deficiency in lymphoid cells. It is our current working hypothesis that the thymus makes a major contribution toward the centrifugal distribution of lymphoid cells which, in turn, is essential to the full expression of immunologic capacity

Transgenic swine lungs expressing human cd59 are protected from injury in a pig-to-human model of xenotransplantation

AbstractBackground: Pulmonary xenotransplantation is currently limited by hyperacute rejection mediated in part by xenoreactive natural antibody and complement. Transgenic swine organs that express the human complement regulatory protein CD59 have demonstrated improved survival in models of pig-to-primate xenotransplantation. Objective: The purpose of this study was to evaluate transgenic swine lungs that express the human complement regulatory protein CD59 in a model of pig-to-human xenotransplantation. Methods: Transgenic swine lungs (n = 5, experimental group) and outbred swine lungs (n = 6, control group) were perfused with fresh, whole human blood through a centrifugal pump on an ex vivo circuit. Functional data were collected throughout perfusion. Immunoglobulin and complement studies were performed on perfusate samples, and both histologic and immunofluorescent analyses were performed on tissue sections. Results: Mean lung survival for the experimental group was increased when compared with controls, 240 ± 0 minutes versus 35.3 ± 14.5 minutes, respectively, with a P value of less than .01. A decreased rise in pulmonary vascular resistance at 15 minutes was observed in the experimental group (343 ± 87 mm Hg · L–1 · min–1, in contrast to the control group (1579 ± 722 mm Hg · L–1 · min–1; P < .01). Pulmonary compliance at 15 minutes was improved for the experimental group versus control group (9.31 ± 1.41 mL · cm–2 H2O and 4.11 ± 2.84 mL · cm–2 H2O, respectively; P < .01). SC5b-9 generation in the plasma perfusate was delayed for the experimental group versus the control group. Immunofluorescent examination of tissue sections demonstrated equivalent deposition of immunoglobulin G, immunoglobulin M, C1q, and C3 in both groups, with reduced deposition of C9 in the experimental group. Conclusions: Transgenic swine pulmonary xenografts that express the human complement regulatory protein CD59 demonstrated improved function and survival in an ex vivo model of pig-to-human xenotransplantation. (J Thorac Cardiovasc Surg 2000;119:690-9

The Pathobiology of the Terminal Complement Complexes

C5b and the other late-acting complement components can assemble the two terminal complexes (TCC) C5b-9 and SC5b-9. In addition to the lytic effects of C5b-9 it has been demonstrated that sublytic amounts of C5b-8 or C5b-9 can stimulate several important cellular activities. These effects may be important to explain the role of C5b-9 in the production and progression of several pathological conditions that has been demonstrated in experimental models of disease. With the help of antibodies that specifically recognize C9 neoantigens, deposits of TCC have been identified in human tissues, not only in immunological diseases but also in certain nonimmunological diseases. In the latter it has been shown that often there is no concordance between deposits of TCC and those of immunoglobulins and C3. Methods for measuring SC5b-9 in biological fluids have also been developed. Normal plasma was found to have low levels of SC5b-9. Increased plasma levels of SC5b-9 have been observed during the active phase of SLE nephritis, in certain infections and during cardiopulmonary bypass. Increased levels were also found in the cerebrospinal fluid of patients with inflammatory diseases of the central nervous system and in the synovial fluid of patients with rheumatoid arthritis. Autoantibodies to C9 neoantigens in plasma of certain patients with autoimmune, infectious or neoplastic diseases have recently been recognized. Additional work is needed to better delineate the potential usefulness of these findings for diagnosis and evaluation of disease activity