Prolongation of second heart transplants in rats.

Second clinical kidney grafts often survive longer than first grafts. Using a rat cardiac allograft model, we examined the conditions under which survival of a second graft can be longer than first graft survival. In the BUF-to-LEW combination, following rejection of the first transplant, second cardiac allografts from the same donor strain implanted immediately survived longer than the first grafts (P = 0.047). Although the mean survival time of first grafts was 9.0 days, second grafts implanted in the same animals survived 19.5 days. In contrast, when ACI donors were used for the same LEW recipients, the second grafts were rejected in 3 days compared with 6.6 days for first grafts. Donor-specific spleen cell transfusions in these combinations resulted in prolonged survival in the BUF to LEW combination, but had no effect when the donor strain was ACI. Second grafts from BUF had prolonged survival following rejection of the first graft. Thus the histocompatibility difference was a determining factor of whether or not prolongation would be obtained. Another factor was timing of the second transplant. If 7 days were allowed to elapse following rejection of the first graft before implantation of the second, the enhancement effect was lost. Moreover, in the LEW-to-ACI combination in which second grafts were rejected rapidly, removal of the first graft after 7 days (before rejection), resulted in prolonged survival of the second graft. There is, therefore, a window of time before rejection of first grafts and shortly thereafter, when the enhancement effect can be obtained. Passive transfer of serum in the BUF-to-LEW combination resulted in enhancement, but transfer of splenic cells was ineffective. We conclude that graft rejection can result in induction of enhancement during a specific period, after which this effect is lost; and that enhancement can be obtained only in certain strain combinations. This suggests that human patients with heart transplants that reject might benefit from a second graft, even from a donor with a mismatch similar to the first graft.     

ICAM-1 deficiency suppresses host allosensitization and rejection of MHC-disparate corneal transplants

BACKGROUND: We used a murine model of orthotopic corneal transplantation to determine whether host deficiency in ICAM-1 promotes survival of corneal grafts with different degrees of allodisparity. METHODS: ICAM-1-/- and wild-type C57BL/6 (ICAM-1+/+) received corneal grafts from the following strains of mice: BALB/c (fully mismatched), BALB.b (mismatched at multiple minor H only), or B10.D2 [including major histocompatibility complex (MHC) mismatch]. Graft rejection, induction of allospecific delayed-type hypersensitivity (DTH) responses, and leukocytic infiltration of grafts were measured. RESULTS: There were no differences in long-term survival of allografts that were either fully mismatched or had only minor H disparity in ICAM-1+/+ vs. ICAM-1-/-hosts. However, whereas B10.D2 grafts were accepted in only 58% of the ICAM-1+/+ hosts, graft survival in ICAM-1-/- recipients was 100% (P=0.006). Moreover, none of the ICAM-1-/- mice receiving B10.D2 grafts developed allospecific DTH. CONCLUSIONS: Prolonged survival seen in MHC-mismatched grafts in ICAM-1-/- mice, along with a suppressed DTH response to donor alloantigens after transplantation, suggest that ICAM-1 is associated with recipient sensitization to MHC alloantigens.     

Factors affecting the outcome of corneal transplantation.

Corneal grafting has been attempted for 200 years. Greatly improved results in recent years have been attributed to developments in anaesthesia, asepsis, and immunological and anti-inflammatory therapy. The important factors affecting the outcome of corneal grafting today are the degree of vascularisation of the cornea before surgery, the inflammatory status at the time of surgery, and the number of antigenic determinants shared by donor and host. Allograft rejection is the most common cause of corneal graft failure. Animal experiments suggest that cyclosporin A given at the time of surgery is likely to prove the most effective means available for preventing corneal graft rejection. Although the introduction of more specific immunosuppressive agents is important, the development of techniques to improve the environment of the outer eye demands the highest priority. Corneal disease is the commonest cause of blindness on a world scale, but many patients are unacceptable for grafting with the currently accepted criteria for operability.     

Reduction in the incidence of rejection of heterotopic murine corneal transplants by pretreatment with ultraviolet radiation

A reduction in the incidence of rejection of mouse heterotopic corneal allografts was achieved by in vitro pretreatment of the graft with ultraviolet light. By day 21, 68% of untreated BALB/c corneas transplanted into s.c. abdominal pouches of C57BL/6 recipients demonstrated rejection. In contrast, corneas pretreated with UV-A, -B, or -C at 150 mJ/cm2 showed an incidence of rejection at day 21 of 30%, 33%, and 18%, respectively. Experiments indicate a significant reduction in rejection with doses of UV-B radiation above 75 mJ/cm2. The mechanism of this reduction is unknown, but may be due to a depletion or alteration of ocular surface Langerhans cells residing in the corneal epithelium.     

Factors related to success or failure of second renal transplants.

From January 1, 1968 to December 31, 1973, 50 patients received two or more kidney transplants. Patient and graft survival was highly dependent upon the source of the donor and to a lesser extent the functional duration of the first transplant and the elapsed time between first and second graft. Survival (patient and graft) was best in patients receiving two related grafts and worst in patients receiving two sequential cadaver grafts. Intermediate rates of success followed cadaver transplantation after rejection of a related graft. The highest failure rate was encountered when those patients who sustained an early loss of the first cadaver graft received a subsequent cadaver graft within a few months. We recommended removal of the acutely rejected graft and delay prior to retransplantation of patients who rapidly reject cadaver grafts in the face of maximal doses of immunosuppression. A delay will permit recovery from both the immunosuppression and any underlying subclinical infections, and will permit the recognition of anti-HL-A antibodies which may not be manifest soon after rejection. Retransplantation of the patient who is slowly rejecting the first kidney does not require prior removal of the rejected graft or delay in retransplantation.     

Phenotypes of antibody-mediated rejection in organ transplants

Antibody-mediated hyperacute rejection was the first rejection phenotype observed in human organ transplants. This devastating phenotype was eliminated by reliable crossmatch technologies. Since then, the focus was on T-cell-mediated rejection and de novo donor-specific antibodies were considered an epiphenomenon of cognate T-cell activation. The immune theory was that controlling the T-cell response would entail elimination of antibody-mediated rejection (ABMR). With modern immunosuppressive drugs, T-cell-mediated rejection is essentially treatable. However, this did not prevent ABMR from emerging as a significant phenotype in all types of organ transplants. It became obvious that both rejection types require distinct treatment and thus reliable diagnosis. This is the current challenge. ABMR, depending on stage, grade, time course, organ type or prior treatment, can present with a wide spectrum of phenotypes. This review summarizes the current diagnostic consensus for ABMR, describes unmet needs and challenges in diagnostics, and proposes new approaches for consideration.     

Chronic rejection of liver transplants revisited

We examined 27 hept-ectomy specimens to assess the frequency of foam cell endovasculitis and bile duct loss in chronic rejection. Arterial lesions, defined as total occlusion by subintimal foam cells and/or fibromuscular proliferation, were found mainly in hilar and septal arteries, whereas bile duct loss, defined as the absence of bile ducts in more than 50% of portal tracts, affected aminly small tracts. Both were found in 20 livers (74%). In two livers (7%) there was significant bile duct loss but no arterial lesions, whilst in five cases (19%) there were occlusive arterial lesions but no bile duct loss. Small arteries were involved in only 10% of the cases. These results indicate that in one-third of the cases arterial and bile duct lesions develop independently of each other, suggesting different pathogenetic pathways. In addition, liver biopsy may not be pathognomonic since small arteries are involved in only 10% of cases and bile duct loss may not be extensive. In such cases the diagnosis of chronic rejection should only be made in the presence of progressive clinical deterioration.     

Rejection of murine heterotopic corneal transplants

A murine heterotopic corneal transplant model has been developed using s.c. abdominal pouches as recipient sites. Donor-recipient genetic disparities involving H-2 antigens alone or H-2 plus non-H-2 antigens result in high rates of rejection. In addition, donor-recipient disparities involving non-H-2 antigens alone or H-Y antigen also result in significant, although lower, rates of rejection. In comparison, pretreatment of the donor grafts by hyperbaric oxygen, removal of the epithelial layer, or soaking in anti-Ia antibody plus complement results in statistically significant reductions in the rejection rates as compared with fresh, untreated donor tissue. These observations suggest that cells bearing Ia antigens (i.e., Langerhans cells) in the epithelial layer of donor corneas play a major role in host sensitization and subsequent rejection following corneal transplantation in this model. However, other antigens may play a role when Ia antigens are depleted from donor corneas.     

Functional monitors of rejection in small intestinal transplants

Absorption of cyclosporine and uptake of radiolabelled glucose by the transplanted small intestine in the dog was investigated to develop physiologic markers of rejection. Cyclosporine in olive oil was given orally, and glucose-14C was instilled into an isolated pouch constructed from the transplanted jejunum. Biopsies were simultaneously obtained from an isolated pouch made from the transplanted ileum. The absorption data were correlated with the histologic findings. Absorption of cyclosporine was of the same magnitude in autotransplanted dogs as it was in allotransplanted dogs with a normal graft. Absorption of cyclosporine in allotransplanted dogs with histologic signs of rejection was significantly reduced. Peak uptake of glucose-14C was noted 5 to 10 minutes after instillation of the isotope in autotransplanted and allotransplanted dogs with a normal graft. Allotransplanted dogs undergoing rejection had a delayed appearance of peak uptake and significantly reduced absolute uptake. In conclusion, absorption of cyclosporine and uptake of radiolabelled glucose can be utilized as functional monitors of intestinal allograft rejection.     

Role of natural killer cells in the rejection process of corneal allografts in rats

BACKGROUND: The exact mechanism of human corneal allograft rejection, which is the major cause of corneal transplant failure, remains unclear. We investigated the role of natural killer (NK) cells in rat corneal allograft rejection by examining the aqueous humor (AH) cell infiltrate on different postoperative days. METHODS: Flow cytometric analysis was performed on the AH and submandibular draining lymph node (DLN) cells before transplantation and at different time points thereafter. In addition, we performed functional cytotoxicity assays with cells present in the AH during corneal rejection. RESULTS: We demonstrated a gradual increase in the absolute cell number of different hematopoietic subpopulations in the AH after allogeneic cornea transplantation. CD3CD4 cells, mainly monocytes and macrophages, were the predominant subpopulation 2 days after transplantation, followed by a successive relative increase of CD4 T cells, CD8 T cells, CD161 T cells, and NK cells. NK and CD161 T cells were present at a 10- to 15-fold higher percentage than in the DLN, suggestive of local expansion of these cells. A higher percentage of NK cells were CD8-negative compared with DLN NK cells. AH cells specifically lysed allogeneic cells, and this cytotoxicity was mainly attributable to NK cells but not to CD4 or CD8 T lymphocytes. CONCLUSION: These results confirm the crucial role of CD4 cells in the allogeneic corneal graft rejection process and implicate NK cells as possible mediators of the rejection.     

Factors affecting rejection of bariatric patients from an academic weight loss program

BackgroundTo determine the factors affecting rejection of bariatric candidates at an accredited, American College of Surgeons Level 1A, bariatric program. Bariatric surgery “Centers of Excellence” use a multidisciplinary team to screen patients for eligibility for surgery using insurance, medical history, psychological evaluation findings, and the surgeon assessment. Few studies have reported on the frequency or reasons for patients not being accepted for surgery among high-volume academic bariatric programs.MethodsFrom March to September 2007, 299 consecutive patients were accepted for evaluation into an accredited bariatric program and tracked for the incidence of rejection for weight loss surgery. The primary reasons for rejection included a lack of insurance coverage, being medically unfit, psychological or social inappropriateness, and a body mass index (BMI) that did not meet the cutoff (BMI <35 kg/m² or <40 kg/m² without co-morbid conditions).ResultsOf 299 screened patients, 90 (30.1%) were not accepted for surgery by the multidisciplinary team. The most frequent reason was the lack of insurance coverage (47.8%). Primary care physicians were the most common source of patient referral. All but 1 of the patients excluded because of an inadequate BMI (n = 13) had been referred by friends, co-workers, or themselves from information received from the Internet or television.ConclusionApproximately one third of screened patients were not accepted for surgery by an academic bariatric program. Self- or social referral appeared to correlate with rejection because the BMI did not meet the criteria for surgery. This suggests inadequate information among social referral networks and/or in the media. Long-term follow-up will determine the health outcomes of patients not cleared for weight loss surgery.     

Macrophages play a role in the early phase of corneal allograft rejection in rats

BACKGROUND: Rat corneal allograft rejection is delayed by repeated local injection of liposomes filled with clodronate (dichloromethylene diphosphonate), which selectively deplete macrophages. Various administration schedules of liposomes were tested to determine the optimum schedule for prevention of graft rejection. Cell subpopulations in the anterior segment of the eye were studied at different time points after transplantation to assess the kinetics of the immune response. METHODS: AO rats were grafted orthotopically with corneal buttons from PVG rats. Postoperatively, rats remained untreated or received clodronate liposomes subconjunctivally. Clodronate liposomes were injected five times on postoperative days (PODs) 0, 2, 4, 6, and 8; or once, on POD 0 or 6; or twice on PODs 0 and 2 or PODs 0 and 6. Grafts were examined for signs of rejection clinically and immunohistologically. RESULTS: All untreated rats rejected their grafts as did all five rats that received clodronate liposomes once on POD 6. In all the other administration schedules tested, graft survival was prolonged compared with the untreated control group (P <0.01). Injections of clodronate liposomes on PODs 0 and 2 proved to be the most effective treatment. Histologically reduced influx of virtually all cell types tested was found in this group. CONCLUSIONS: To prevent or delay graft rejection, it is necessary to administer clodronate liposomes in the early phase after corneal transplantation. These results suggest a role for macrophages in the afferent phase of corneal graft rejection.     

Acute humoral rejection of renal transplants in alloimmunized pigs

BACKGROUND: Despite progress in immunosuppression, acute humoral rejection (AHR) remains an unsolved issue in transplantation, with a possible reversibility in only about 50% of cases. AHR is characterized by antidonor antibodies in the recipient circulation and characteristic histological lesions within the graft itself, as well as complement degradation products and immunoglobulins (IgM and IgG) deposition in vascular zones. The lack of a large animal models of AHR in experimental allotransplantation led us to establish such a model in the pig. MATERIALS AND METHODS: Pigs were immunized with peripheral blood mononuclear cells from allogeneic donors and subsequently received a kidney from the same donor, once antidonor antibodies (Ab) had reached a plateau. The efficiency of the alloimmunization, the nature of the induced antibodies and rejection were studied. RESULTS: Six out of seven recipients developed specific antidonor Ab. Three days post-transplantation, characteristic lesions of AHR were observed together with intragraft IgG, IgM, and complement deposition. The AlloAb were found to be cytotoxic and directed against donor MHC class I molecules. CONCLUSIONS: We described, for the first time, a large animal model of AHR, which will enable us to more extensively study phenomena implicated in AHR and to test new strategies aimed at its prevention or cure, as well as improve transplant protocols in the case of presensitized or hyperimmunized patients.