Administration of an anti-interleukin 2 receptor monoclonal antibody prolongs cardiac allograft survival in mice.

Administration of the monoclonal antibody M7/20, which binds to the murine interleukin-2 (IL) receptor, significantly prolongs cardiac allograft survival in two H-2-incompatible strain combinations of inbred mice. The results support the important role of the IL-2 receptor in the mechanism of graft rejection, and suggest its suitability as a target for immunosuppressive therapy.

Structural and functional evolution of jejunal allograft rejection in rats and the ameliorating effects of cyclosporine therapy.

We assessed the structural and functional evolution of small intestinal transplant rejection in a rat model by use of 1-micron section, electron microscopic, and in vitro electrophysiologic techniques to study jejunal mucosa 3, 6, and 9 d posttransplantation. The earliest structural abnormalities detected in jejunal loops transplanted from Lewis X Brown Norway F1 hybrids into Lewis rats occurred within 3 d posttransplantation and consisted of focal endothelial cell injury of the microvasculature and focal injury of crypt epithelial cells. Both alterations were associated with adjacent infiltration of large lymphoid cells, and both markedly progressed and became rather diffuse over the following 6 d. In contrast, villus absorptive cells were not markedly altered in structure until the 9th postoperative day. As compared with host jejuna, allograft jejunal epithelium demonstrated multiple functional abnormalities. Transepithelial resistance declined progressively by days 6 and 9 (both P less than 0.05), although baseline transepithelial spontaneous potential difference was only affected at day 9 (P less than 0.01). Stimulated absorption by allograft jejuna, as assessed by measuring electrical response to mucosal glucose, was not significantly diminished until day 9 (P less than 0.05). In contrast, stimulated secretion assessed by measurement of electrical response to serosal theophylline was diminished by day 6 (P less than .01). These data suggest that the earliest epithelial injury during rejection, as judged both structurally and functionally, occurs in the crypt and is paralleled by endothelial injury at the level of the microvasculature. Thus, the primary targets for rejection are most likely endothelial cells and crypt epithelial cells. In contrast, structural and functional impairment of villus epithelium is detectable only at substantially later times during rejection and are most likely secondary processes related to either ischemia produced by microvascular injury or decreased epithelial regenerative ability secondary to crypt injury. Last, we show that the detrimental structural and functional sequellae of jejunal transplantation across the major histocompatibility complex in this model is strikingly ameliorated with cyclosporine therapy.

In vivo localization of [(111)In]-DTPA-D-Phe1-octreotide to human ovarian tumor xenografts induced to express the somatostatin receptor subtype 2 using an adenoviral vector.

Adenoviral vectors, encoding genes for cell surface antigens or receptors, have been used to induce their high level expression on tumor cells in vitro and in vivo. These induced antigens and receptors can then be targeted with radiolabeled antibodies or peptides for potential radiotherapeutic applications. The purpose of this study was to determine a dosing schema of an adenoviral vector encoding the human somatostatin receptor subtype 2 (AdCMVhSSTr2) for achieving the highest tumor localization of [(111)In]-DTPA-D-Phe1-octreotide, which binds to this receptor, in a human ovarian cancer model as a prelude to future therapy studies. AdCMVhSSTr2 was produced and used to induce hSSTr2 on A427 human nonsmall cell lung cancer cells and on SKOV3.ipl human ovarian cancer cells in vitro, as demonstrated by competitive binding assays using [125I]-Tyr1-somatostatin and [(111)In]-DTPA-D-Phe1-octreotide. Mice bearing i.p. SKOV3.ip1 tumors administered 1 x 10(9) plaque-forming units of AdCMVhSSTr2 i.p. 5 days after tumor cell inoculation, followed by an i.p. injection of [(111)In]-DTPA-D-Phe1-octreotide 2 days later, showed a range of 15.3-60.4% median injected dose/gram (ID/g) in tumor at 4 h after injection compared with 3.5% ID/g when [125I]-Tyr1-somatostatin was administered and 0.3% ID/g when the negative control peptide [125I]-mIP-bombesin was administered. Mice administered a control adenoviral vector encoding the gastrin-releasing peptide receptor did not have tumor localization of [(111)In]-DTPA-D-Phe1-octreotide (<1.6% ID/g), demonstrating specificity of [(111)In]-DTPA-D-Phe1-octreotide for the AdCMVhSSTr2 induced tumor cells. In another set of experiments, the tumor localization of [(111)In]-DTPA-D-Phe1-octreotide was not different 1, 2, or 4 days after AdCMVhSSTr2 injection (31.8, 37.7, and 40.7% ID/g, respectively; P = 0.88), indicating that multiple injections of radiolabeled peptide can be administered with equivalent uptake over a 4-day period. [(111)In]-DTPA-D-Phe1-octreotide tumor localization in animals administered AdCMVhSSTr2 on consecutive days or 2 days apart was 22.4% ID/g and 53.2% ID/g, respectively (P = 0.009) when [(111)In]-DTPA-D-Phe1-octreotide was given 1 day after the second AdCMVhSSTr2 injection. There was no difference in [(111)In]-DTPA-D-Phe1-octreotide localization after a single AdCMVhSSTr2 injection (40.7% ID/g) or two injections of AdCMVhSSTr2 given 1 (45.9% ID/g) or 2 (53.2% ID/g) days apart, where [(111)In]-DTPA-D-Phe1-octreotide was given in each case 4 days after the first AdCMVhSSTr2 injection (P = 0.65). Therefore, two AdCMVhSSTr2 injections did not increase [(111)In]-DTPA-D-Phe1-octreotide tumor localization compared with one injection, which eliminates concerns about an immune response to a second dose of AdCMVhSSTr2. This will be the basis for a therapeutic protocol with multiple administrations of an octreotide analogue labeled with a therapeutic radioisotope.

Immune function in transplanted small intestine. Total secretory IgA production and response against cholera toxin.

Secretory IgA is the dominant immunoglobulin produced in the small intestine and one important component of the local defense against dietary and infectious agents present in the gut lumen. The effect of small intestine transplantation on total production of sIgA and on the response to a newly presented antigen, cholera toxin, was determined in a rat segmental heterotopic intestinal transplant model. Lewis x Brown Norway F1 (LBNF1) allografts in Lewis hosts made normal amounts of sIgA, when compared with LBNF1 Thiry-Vella loops or LBNF1 isografts. In contrast, the allografts failed to make a significant specific sIgA response when immunized with cholera toxin at days 0 and 7 following transplantation. This failure was not the result of surgical manipulation, as isografts made normal amounts of specific sIgA directed against cholera toxin. Cyclosporine immunosuppression delayed, but did not prevent, the secretion of specific antibody in isografts. This failure to respond to a new antigen may have important implications for the safety of small bowel transplantation.

Evidence that rapamycin inhibits interleukin-12-induced proliferation of activated T lymphocytes.

Interleukin 12 is a heterodimeric cytokine involved in the regulation of natural killer cell and T lymphocyte responses. In previous studies, we found that IL-12 induces proliferation of T cells only after co-stimulation with lectin, alloantigen, or anti-CD3 antibody. The IL-2-mediated proliferation of long-term T cell lines generated in this fashion is typically insensitive to the immunosuppressive agent, cyclosporine but sensitive to rapamycin. In this study, we examined the effect of cyclosporine and rapamycin on T cells responsive to IL-12. For long-term cultured T cell lines stimulated with phytohemagglutinin, alloantigen, or solid-phase anti-CD3 antibody, rapamycin blocked IL-12-induced proliferation to background levels. Culture in cyclosporine produced minimal inhibition of IL-12-induced T cell proliferation. Freshly isolated CD3+ cells did not proliferate in response to IL-12, nor did culture of these cells in IL-12 lead to upregulation of IL-2 receptor. These data suggest that the effect of IL-12, an important growth regulator for activated T lymphocytes, may involve late cellular activation events.

Interleukin 2 receptor expression on peripheral blood lymphocytes in association with renal allograft rejection.

Periodic assay of IL-2 receptor expression on the surfaces of peripheral blood lymphocytes might provide information predictive of in vivo immunologic events. This study compares two methods of determining IL-2 receptor expression after renal transplantation in cynomolgus monkeys. The first utilized single color staining of peripheral blood mononuclear cells with mouse anti-human IL-2 receptor monoclonal antibody followed by a fluorescein-labeled goat anti-mouse IgG antibody. Epics C cell sorter windows were set to count cells of the size and granularity of normal lymphocytes. The second utilized two-color staining with fluorescein-labeled anti-IL-2 receptor antibody, combined with phycoerythrin-labeled anti-CD4 antibody or with phycoerythrin-labeled anti-CD8 antibody. Two-color staining allowed the sorter windows to be enlarged to count all mononuclear cells, regardless of size or granularity, without introducing the contaminating effects of monocytes. Data obtained from single-color staining showed no consistent or significant expression of the IL-2 receptor on peripheral lymphocytes in association with the rejection process. Data obtained from two-color staining revealed an increase of IL-2 receptor expression on peripheral T cells of at least 10% from the postoperative baseline, which preceded the creatinine rise from allograft rejection in 13 of 13 animals. Increases in IL-2 receptor expression on T cells were not specific to rejection, however. Some animals in which treatment produced a delay of rejection showed a transient rise in IL-2 receptor expression around post-transplant day 5, which was not followed by a rise in creatinine. The two-color staining technique described provides a sensitive means of detecting IL-2 receptor expression in vivo and documents the association of increases in IL-2 receptor expression on T cells with rejection.

Transplantation in miniature swine. VII. Evidence for cellular immune mechanisms in hyperacute rejection of renal alografts.

Renal allografts were performed in miniature swine that were identical at their major histocompatibility locus and were presensitized by skin grafts from their prospective renal donors. All of these renal grafts were rejected in a hyperacute or markedly accelerated manner compared to the survival of comparable grafts in nonsensitized animals. Studies directed at the mechanism of this rejection revealed no circulating recipient antidonor antibodies by several serological assays. In contrast, mixed lymphocyte cultures (MLCs) and cell-mediated lympholysis (CML) assays demonstrated marked recipient antidonor lymphocyte reactivity that appeared after skin grafts, diminished during the tenure of the renal graft in the host circulation, and reappeared after removal of the rejected kidney. These results suggest that cellular immune mechanisms may plan a role in the accelerated rejection of major histocompatibility complex (MHC)-identical renal allografts.

Prolongation of cardiac allograft survival in murine recipients treated with a diphtheria toxin-related interleukin-2 fusion protein.

A diphtheria toxin-related IL-2 fusion gene has been constructed that encodes a 68KD recombinant toxin in which the diphtheria toxin receptor-binding domain has been replaced with amino acids 2-133 of IL-2. This chimeric IL-2 toxin is cytotoxic for cells expressing the high-affinity IL-2 receptor but not for cells lacking this receptor. The ability of this IL-2 toxin to prolong allograft survival was examined in a murine vascularized, heterotopic heart transplant model in the strain combination B10.BR into C57B1/10. When given at a dose of 1.0 micrograms/day for 10 days, the IL-2 toxin significantly prolonged allograft survival in all recipients. CRM-45, a fragment of diphtheria toxin missing the binding domain, was ineffective, confirming the specificity of the therapy. The results demonstrate that this IL-2 toxin, which targets activated T cells expressing the IL-2 receptor, will prolong allograft survival, offering a new option for immunosuppressive therapy.

Enhancement of immunosuppression by substitution of fish oil for olive oil as a vehicle for cyclosporine.

As previously reported, acute cyclosporine-induced nephrotoxicity is characterized by a decline in glomerular filtration rate and a selective intrarenal production of the vasoconstrictor thromboxane (TxA2), but not vasodilator prostaglandin E2 (PGE2), or prostacyclin (PGI2), cyclooxygenase metabolites. Fish oils (FO), that are rich in n-3 polyunsaturated fatty acids have a high affinity for cyclooxygenase but serve as poor substrate inhibit TxA2 synthesis. We have shown that when FO replaces olive oil (OO) as the vehicle for CsA, CsA-induced nephrotoxicity and increased TxA2 synthesis are obviated in rodent models. In this study, we demonstrate that the FO vehicle for CsA does not compromise CsA's immunosuppressive properties as deduced from studies of a delayed-type hypersensitivity (DTH) model in BALB/c mice and in a rat heart transplant model. In fact, concurrent FO administration with CsA actually enhances immunosuppression. A dose of CsA incapable of blunting DTH when injected in OO was suppressive when given in FO. Administration of as little as 0.05 ml of FO vehicle potentiated the suppressive action of CsA. In addition, nonconcurrent dietary supplementation of FO in animals receiving CsA caused an increase in the immunosuppressive action of CsA in DTH. FO alone reduced DTH as compared with OO, but was far less effective than CsA plus FO. Furthermore, doses of CsA (5 mg/kg/day or 1.5 mg/kg/day), which are subtherapeutic when administered with OO, prolonged engraftment of Lewis recipients of Lewis x Brown-Norway F1 hearts when CsA was solubilized with FO. These studies indicate that concurrent administration of CsA and FO potentiates the activity of CsA and thus increases its therapeutic index. Thus, CsA plus FO is potentially a safe, potent antirejection therapy worthy of clinical testing, especially insofar as FO prevents CsA-induced acute nephrotoxicity in the rodent.

Late mortality and morbidity in recipients of long-term renal allografts.

The experience of the Peter Bent Brigham Hospital with 217 renal allografts functioning for more than 5 years is reviewed. Patient and graft survival were similar after 5 years, with patient survival being 88 and 66% at 10 and 15 years, respectively, and graft survival 85 and 75% at the same time intervals. Actuarial graft survival at 15 years was higher than patient survival because death with a functioning graft was not considered to be graft failure. No differences in patients or graft survival were found between living related and cadaver donor allografts. There were 33 deaths (15.2%), occurring from 5 1/2 to 20 1/2 years post-transplantation. Chronic liver failure and sepsis were the most common causes of death. Thirty-two patients (14.7%) lost their grafts after 5 years, most commonly from chronic rejection. Another 33 patients (15.2%) had evidence of graft dysfunction secondary to chronic rejection, recurrent glomerulonephritis, ureteral obstruction, or renal artery stenosis. Chronic rejection was generally not responsive to alterations in immunosuppressive medication. Complications of varying severity were common affecting 204 (94%) of the patients. The most frequent were hypertension, cataracts, avascular necrosis, malignancy, urinary tract infection, and pneumonia. These data demonstrate that transplant-related mortality and morbidity continue to occur in recipients of long-term renal allografts. These patients require careful and continuing care in medical centers experienced in transplantation.

Conversion from cyclosporine to azathioprine in renal allograft recipients.

Fifty seven recipients of renal allografts initially treated with CsA and low-dose prednisone were switched to azathioprine and low-dose steroids. Ten had prolonged (greater than 28 days) allograft nonfunction after transplantation (group 1), 8 had ongoing, poorly controlled rejection (group 2), and 39 had stable functioning grafts (group 3). With a mean follow-up period of 5 +/- 3 months after conversion, 50 grafts remained functional including 6 of 10 in group 1, 6 of 8 in group 2, and 38 of 39 in group 3. Thirty-seven (65%) had improved function, 12 (21%) had stable function, and 8 (14%) experienced declining renal function. Three of these latter 8 patients required reinstitution of CsA therapy. There were 20 episodes of acute rejection in 18 patients; one graft lost function because of acute rejection unresponsive to therapy. Reasons for the 6 other graft losses were persistent primary nonfunction in 3 patients from group 1, untreated rejection in 2 patients who had multiple prior rejection episodes while on CsA, and chronic rejection in one patient. Although renal function has improved or stabilized in the majority (86%) of individuals changed to azathioprine therapy, there was substantial risk of acute rejection (32%) complicating this procedure. Patients most likely to benefit from conversion to azathioprine therapy are those with prolonged graft nonfunction after transplantation and those with serum creatinines greater than 2.0 mg/dl.

Transplantation in miniature swine. X. Evidence for non-SLA-linked immune response gene(s) controlling rejection of SLA-matched kidney allografts.

The survival of renal allografts between SLA-matched swine has been found to be subject to non-SLA-linked Ir gene control. Using three herds of miniature swine, each homozygous for a different SLA haplotype (designated aa, cc, and dd, respectively), we initially observed that all animals of the c haplotype rejected SLA-matched renal allografts. In contrast, the subset of dd animals which were the product of continuous homozygous matings since establishment of the dd herd (ddR) accepted SLA-matched grafts indefinitely without any immunosuppression. A formal backcross study was therefore performed in which offspring of (cd x ddR) matings (designated cdbc and ddbc) were bilaterally nephrectomized and transplanted with SLA-matched renal allografts. Acceptors and rejectors were found among both backcross types, with a total of 6 of 17 (35%) of the animals dying of renal failure secondary to rejection. When ddbc animals were used as donors for ddR recipients, all grafts were accepted, ruling out the possibility that rejection was attributable to strong non-SLA antigens segregating within the cc herd. These results are consistent with a model in which rejection of SLA-matched renal allografts is controlled by either one or two non-SLA-linked immune response genes. These findings raise the possibility that the observed 5 to 15% frequency of rejection of HLA-identical living related donor renal allografts in man could involve similar immune response gene control.

Transplantation in miniature swine. VI. Factors influencing survival of renal allografts.

Renal allografts were performed between and among animals from three herds of miniature swine that were selectively inbred to homozygosity at the major histocompatibility complex, MSLA. The results suggest several genetic factors which influence the survival of renal allografts in these animals. As expected, the major histocompatibility complex (MHC) was of dominant importance, and all MSLA-mismatched grafts were rejected promptly (12 +/- 3.7 days). Some MSLA-matched grafts were also rejected (30 +/- 15.0 days), indicating that non-MSLA loci also determine antigens which can lead to kidney rejection. Other MSLA-matched grafts were accepted indefinitely. At least one immune response gene that determined ability to reject kidneys across non-MSLA differences seemed to be segregating in our swine population. Animals that had accepted MSLA-matched renal grafts for extended periods demonstrated markedly prolonged survival of subsequent donor skin grafts compared to skin graft survival across the same non-MSLA difference in normal animals. This finding suggests that failure to reject kidneys across non-MSLA differences indicates systemic tolerance, and that there may be a relationship between the induction of such tolerance and the proposed immune response gene controlling rejection.

The effect of anti-interleukin-2 receptor monoclonal antibody on allograft rejection.

During immune response to an allograft, activated T cells express a number of cell surface activation antigens, among them the membrane receptor for the lymphokine interleukin 2 (IL-2). As the IL-2 receptor is not present on resting T cells, it offers an attractive target for potentially specific immunosuppressive therapy. The rat monoclonal antibody M7/20, which binds to the murine IL-2 receptor, was studied for its effect on allograft survival in two H-2-incompatible strain combinations in inbred mice. Treatment with M7/20 for 10 days markedly prolonged survival of vascularized, heterotopic heart allografts in both strain combinations, with indefinite graft survival in 50% of recipients. The same treatment significantly prolonged skin allograft survival in one of the two combinations. The results support the important role of the IL-2 receptor in the mechanism of graft rejection and confirm its suitability as a target for immunosuppressive therapy in transplantation.

Differential IL-2 receptor expression in renal allograft recipients treated with an anti-IL-2-receptor antibody.

Patients were entered into a randomized trial of prophylaxis for renal allograft rejection by the administration of an anti-human IL-2 receptor antibody, anti-Tac, during the first ten days posttransplant. Interleukin-2 receptor (IL-2 R) expression was measured using two anti-IL-2 R monoclonal antibodies (moAbs), anti-Tac and 1HT4-4H3. These two antibodies recognize closely spaced epitopes on the 55 kD chain of the IL-2 R. IL-2 R expression was examined on peripheral blood small lymphocytes in three groups of patients who received: (A) cyclosporine CsA and prednisone for baseline immunosuppression (n = 9); (B) anti-Tac with CsA and prednisone as baseline immunosuppression (n = 12); and (C) anti-Tac with azathioprine and prednisone as baseline immunosuppression (n = 5). We found that large numbers of T cells express IL-2 receptors despite the presence of anti-Tac (average of IL-2 R-positive cells at day of peak IL-2 R expression 56.0 +/- 20.8% in group A, 65.2 +/- 26.6% in group B, 21.0 +/- 7.4% in group C). IL-2 R expression did not correlate with clinical activity, and the presence or accessibility of epitopes on the same 55 kD chain varied dramatically from patient to patient.

Treatment of acute renal allograft rejection with monoclonal anti-T12 antibody.

Nineteen patients with acute rejection of a renal allograft were treated with the monoclonal antibody anti-T12, directed against a determinant present on all post-thymic T cells. Seven patients had a good response, four had an equivocal response, and eight failed to respond. Histologic studies demonstrated that the good responders had primarily cellular rejection. The nonresponders included 4 patients with moderate-to-severe humoral rejection, one patient with an inadequate dose of antibody, one patient who withdrew before completing the study, and one patient with late end-stage rejection. All eleven patients with good or equivocal responses have functioning kidneys in a follow-up of 1-15 months (mean 7 months). Only one patient has had a subsequent acute rejection episode, which responded to a steroid pulse. No significant complications of anti-T12 therapy occurred.

A randomized prospective trial of anti-Tac monoclonal antibody in human renal transplantation.

Patient entry is now complete in a prospective trial of anti-Tac, a murine IgG2a monoclonal antibody directed against the p55 chain of the human IL-2 receptor, for the prevention of renal allograft rejection. Recipients of primary cadaver allografts were randomized to receive either anti-Tac (20 mg q.d. x 10 days beginning POD 1) plus low-dose CsA (4 mg/kg/day), azathioprine (2 mg/kg/day), and prednisone (30 mg q.d.), or conventional triple therapy with CsA (8 mg/kg/day), azathioprine, and prednisone. Forty patients were entered in each group, with current followup from 6 to 26 months. The results show a significant reduction in early rejection episodes in the anti-Tac-treated patients. During the 10-day treatment, 5 of 40 anti-Tac patients had rejection episodes, compared with 21 of 40 control patients (P less than 0.001). Anti-Tac significantly delayed the time to the first rejection (12.5 +/- 6.3 vs. 7.6 +/- 6.7 days) (P less than 0.05). Despite these effects, there were no differences in either actual or actuarial graft or patient survival between the two groups. Pneumonia, primarily CMV, developed in 5 treated and 4 control patients. In patients with functioning grafts mean serum creatinine at 3 months was 1.8 +/- 0.7 in the anti-Tac group and 2.0 +/- 0.8 in the control group (P = NS); at 12 months the values were 2.3 +/- 1.5 and 1.8 +/- 0.5, respectively (P = NS). The peak expression of IL-2 receptors on circulating T-cells was significantly lower in anti-Tac patients (15.1 +/- 3.6%) than in controls (21.9 +/- 4.5%) (P less than 0.05). Seven of 10 patients tested to date developed antimouse immunoglobulin antibodies, with antiidiotype shown in 6. These antibodies do not preclude subsequent treatment with OKT3. Five patients in this and previous anti-Tac protocols have received OKT3 for acute rejection despite known pretreatment antimouse antibodies, with resolution of rejection in all cases.

Prolongation of primate renal allograft survival by anti-Tac, an anti-human IL-2 receptor monoclonal antibody.

In an effort to produce specific immunosuppression through the targeting of those lymphocytes expressing cell surface interleukin 2 receptors in response to an allograft, the anti-human IL-2 receptor monoclonal antibody anti-Tac was administered to cynomolgus monkeys receiving renal transplants. The data demonstrate that anti-Tac produces a significant delay in renal allograft rejection and prolongs host survival in cynomolgus monkeys. Though higher doses of anti-Tac produce modest delays in rejection, there was a surprising finding of greatly prolonged survival in three of five monkeys treated with much lower doses of anti-Tac. Anti-Tac was not shown to be synergistic with cyclosporine in this model. Animals treated with anti-Tac developed high titers of antibodies against the murine monoclonal antibody after 6-8 days of treatment, associated with the disappearance of plasma anti-Tac staining of activated lymphocytes as measured by flow cytometry. The data confirm the utility of the IL-2 receptor as a target for immunosuppressive therapy, and suggest that investigations of dosage and of methods to reduce the immunogenicity of anti-IL-2 receptor agents may be beneficial.

The detection of cardiac allograft rejection by alterations in proton NMR relaxation times.

The ability of proton NMR relaxation times to detect cardiac allograft rejection was studied in an inbred rat heterotopic cardiac transplantation model. Hearts from 25 Lewis X Brown Norway F1 hybrid rats were anastomosed to the abdominal aorta and vena cava of Lewis recipients; 25 Lewis donor hearts served as isograft controls. Groups of five allografts and five isografts were harvested daily between two and six days post-transplant. The relaxation times T1 and T2 of the transplanted hearts were determined in vitro with a 10 MHz spectrometer. T1 and T2 values in allografts did not differ significantly from those in isografts at days 2 and 3 post-transplant. However, at days 4, 5, and 6 T1 and T2 of the allografts were significantly prolonged. This finding correlated with an elevation in tissue water content and the onset of rejection as determined histologically. An additional 21 allografts, treated with cyclosporine, were studied in the same way from four to more than 100 days post-transplant. T1 and T2 values of these treated allografts did not change significantly during the observation period and were similar to the relaxation values obtained in the isografts at days 2 to 6. These data suggest that serial measurements of myocardial T1 and T2 may be useful in detecting acute cardiac allograft rejection and monitoring the effect of antirejection treatment.

Small intestine transplantation in the rat--immunology and function.

Heterotopic, vascularized small intestine transplants were performed in inbred strains of rats to investigate the structural, functional, and immunologic consequences of intestinal transplantation with and without immunosuppression with cyclosporine (CyA). Lewis X Brown Norway F1 intestine was rejected by untreated Lewis recipients in 7 to 10 days. Structurally, rejected intestine was characterized by shortened crypts and villi lined by damaged attenuated epithelial cells. Functionally, rejection was associated with impaired epithelial active ion transport as indicated by decreased potential difference and with diminished epithelial barrier function as reflected by decreased transepithelial resistance. Administration of CyA for 7 days prevented clinical rejection and partially prevented the structural and functional defects. Lewis intestine transplanted into Lewis X Brown Norway F1 recipients caused fatal graft versus host disease (GVHD) in 9 to 17 days. Treatment with CyA for 7 days failed to prevent GVHD routinely, but prolonged administration delayed fatal GVHD until CyA was discontinued. Intestine from Lewis "B" rats made deficient of T cells by thymectomy, irradiation, and reconstitution with syngeneic T cell-depleted bone marrow failed to cause GVHD in Lewis recipients. Reconstitution of the "B" rats with T cells before transplantation restored the GVHD response. These results may be relevant in the consideration of clinical small intestinal transplantation.