Time Course Of Rejection Research Articles

Mouse kidney transplantation: models of allograft rejection.

Rejection of the transplanted kidney in humans is still a major cause of morbidity and mortality. The mouse model of renal transplantation closely replicates both the technical and pathological processes that occur in human renal transplantation. Although mouse models of allogeneic rejection in organs other than the kidney exist, and are more technically feasible, there is evidence that different organs elicit disparate rejection modes and dynamics, for instance the time course of rejection in cardiac and renal allograft differs significantly in certain strain combinations. This model is an attractive tool for many reasons despite its technical challenges. As inbred mouse strain haplotypes are well characterized it is possible to choose donor and recipient combinations to model acute allograft rejection by transplanting across MHC class I and II loci. Conversely by transplanting between strains with similar haplotypes a chronic process can be elicited were the allograft kidney develops interstitial fibrosis and tubular atrophy. We have modified the surgical technique to reduce operating time and improve ease of surgery, however a learning curve still needs to be overcome in order to faithfully replicate the model. This study will provide key points in the surgical procedure and aid the process of establishing this technique.

Lung Transplantation in the Fischer 344→Wistar Kyoto Rat Strain Combination is Not Suitable to Study Bronchiolitis Obliterans

To elucidate the pathogenesis of bronchiolitis obliterans (BO) a reliable animal model is needed. According to the literature, lung transplantation from Fischer 344 (F344) to Wistar Kyoto (WKY) rats is the only model that reliably results in BO without a further stimulus. We performed orthotopic left lung transplantation in F344 to WKY rats and in both isogeneic rat strain combinations. Suture and cuff techniques for anastomosis were compared. The time course of rejection and the morphology of the bronchial anastomoses were documented by repeated flat-panel volumetric computed tomography (fpVCT) in the living animal. Graft histopathology was analyzed 3 months post-transplant. According to the graft outcome, as revealed by fpVCT, grafts were sub-divided into two groups: In Group 1, infiltrates due to acute rejection occurred early after transplantation and resolved thereafter. Graft histopathology showed minor changes but no BO. In Group 2, acute rejection caused total atelectasis that never resolved. After 3 months, grafts were shrunken and exhibited tissue remodeling with some similarities to BO. No correlation between graft outcome and anastomotic technique was apparent. Modeling lung transplantation using the F344-to-WKY combination is without clinical relevance because BO does not develop in grafts with life-sustaining function. Consecutive fpVCT is useful to monitor pathologic changes in rat pulmonary grafts.

Rejection patterns in allogeneic uterus transplantation in the mouse

Transplantation of the uterus in the mouse has been developed as a model system for research towards human uterine transplantation. Previous studies in a mouse model have demonstrated that a syngeneic uterus transplant can give rise to normal offspring. The aim of this study was to characterize the time course of rejection in a fully allogeneic mouse uterus transplantation model. Uteri of BALB/c mice were transplanted to a heterotopic position in C57BL/6 recipients, whose native uteri were left in situ. The blood flow of the uteri, their gross appearance and general histology and the density of T-lymphocytes were examined on postoperative days 2-28. Macroscopic signs of rejection were apparent from day 5. At the light microscopy level, minimal inflammatory changes were seen from day 5 and massive inflammation was seen from day 10 to day 15. At day 28, necrosis and fibrosis were seen. The density of T-lymphocytes (CD3(+)) was increased in the grafted uterus from day 2 in the myometrium and from day 5 in the endometrium. Blood flow in the grafted uteri was reduced from day 15. A murine model to study rejection of allogeneic uterus transplants was characterized. Signs of rejection were seen from day 2 to day 5 and severe rejection was seen from day 10 to day 15. The data will be useful in future studies on immunosuppressants in this model.

Induction and tolerization of anti-male CD8 + cytotoxic T lymphocytes by in vivo immunization with an H-Y-derived peptide

We have analyzed the immune response induced by a 9mer synthetic peptide derived from the male histocompatibility antigen H-Y and containing D b-binding motifs in C57BL/6 mice. In this study we report that a single, subcutaneous injection of the peptide emulsified in IFA gave rise to the development of male-specific CD8 + T cells which displayed H-Y-specific proliferative response in vitro and showed a Tc1-type pattern of cytokine production (i.e. they secreted IFN-γ and IL-2, but not IL-4 and IL-10). Development of a strong cytotoxic activity required in vitro stimulation with specific peptide and IL-2: under these culture conditions, we were able to generate potent CD8 + CTLs that lysed both male cells and peptide-pulsed female cells. Continuous administration of soluble peptide, delivered over a 7-day period by a mini-osmotic pump implanted subcutaneously, inhibited proliferative and cytotoxic responses and IFN-γ production in lymph node cells from C57BL/6 mice subsequently primed with peptide in adjuvant. This decreased responses were associated with a strong increase in the secretion of IL-4 by antigen-specific CD8 + T lymphocytes. Subcutaneous administration of the H-Y-peptide in adjuvant significantly accelerates rejection of male skin graft, while continuous administration of peptide in soluble form did not modify the time course of rejection.

Pregnancy after autografting and allografting vascularized ovaries and en bloc vascularized ovaries with adnexa in rabbits

Initially, techniques for autografting ovaries with or without adnexa were developed but a 30% vascular failure rate was experienced by day 14. Of the technically successful grafts, 50% proved fertile. Single vascularized ovaries with their oviducts were then allografted into bilaterally ovariectomized rabbits by microsurgical techniques and the vascular failure rate was reduced to 5% of 40 grafts. The time-course of rejection in untreated recipients was mapped by histological examination and by 24-h culture of fallopian tubes after autopsy at different times after transplantation. Control allografts were consistently rejected by day 20. Striking prolongation of both types of graft was obtained with a short 17-day course of cyclosporin A at 10 or 15 mg day-1 kg-1. Indeed, significant evidence of rejection was found in only two ovaries out of 20 so far examined histologically. Mating behaviour, ovulation, ciliary function and transport of ova appeared normal in 80% of the recipients as long as 18 weeks after stopping cyclosporin A treatment. Only one of the ovarian allografted rabbits has so far been mated and this produced seven normal young 126 days after transplantation. However, none of the five animals mated after being allografted with en bloc adnexa have so far become pregnant.

Islet transplantation in mice differing in the I and S subregions of the H-2 complex. Effects of presensitization with skin allografts.

Pancreatic islets from A.TH mice were transplanted into the spleen of streptozotocin (SZ)-diabetic A.TL mice. The two strains of mice are congenic inbred strains, differing only in the I and S subregions of the H-2 complex. The allogeneic islet grafts decreased blood glucose temporarily, but the islets were rejected after 21 +/- 7 days (mean +/- SD). The effect of skin presensitization was tested by giving both allogeneic and syngeneic skin grafts to each of a second set of A.TL mice before streptozotocin treatment and islet transplantation. The time course of rejection of the allogeneic islets in animals that received initial skin grafts was decreased to 8 +/- 3 days. In both skin-presensitized and non-presensitized mice syngeneic islet grafts were able to restore normoglycaemia, even in animals that had previously rejected an islet allograft. These observations demonstrate that transplantation of pancreatic islet allografts across the I and S subregions of the H-2 complex is sufficient to induce rejection of the islets. The islet rejection was markedly accelerated by prior sensitization with allogeneic skin grafting. It is suggested that elements in allogeneic skin grafts serve as inducers of cytotoxic T-cell responses directed against gene products of the I and/or S subregions present on cells in the allogeneic islets.

Histopathology and time course of rejection of allografts of mouse small intestine.

SUMMARY Grafts of foetal mouse small intestine were implanted heterotopically under the kidney capsule in adult allogeneic mice and subsequently examined histologically to determine the features and time course of rejection. Grafts healed in, grew, and developed normally for a few days. The earliest sign of rejection was the appearance of lymphocytes in the graft lamina propria. Later, there was extensive lymphocyte infiltration of the full thickness of the intestine. Many tissues had the general mucosal morphology of partial or subtotal villous atrophy. Later, there was complete destruction of the mucosa, and the remnants of the grafts consisted of smooth muscle heavily infiltrated with lymphocytes and plasma cells. These same events occurred in sequence in all the strain combinations studied but the time course of rejection varied with histocompatibility differences between donor and host strains. Thymus-deprived mice showed profoundly impaired ability to reject allografts. The relevance of these observations to the histopathology of coeliac disease is discussed.