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Recurrent glomerulonephritis in transplanted kidneys is not rare despite classical immunosuppressive drugs and depends on the etiology of nephropathy. Treatment of recurrence of renal disease on graft remains controversial. We report 6 cases of patients with recurrent glomerulonephritis after renal transplantation treated with mycophenolate mofetil (MMF). The glomerular diseases were Wegener's granulomatosis (n = 1), membranoproliferative glomerulonephritis type I (n = 1), focal and segmental glomerular sclerosis (n = 1), membranous glomerulonephritis (idiopathic membranous nephropathy (n = 1) and systemic lupus erythematous) (n = 1)) and immunoglobulin A nephropathy (n = 1). MMF was introduced because of intolerance of classical immunosuppressive treatment in 2 cases and because of its inefficiency in the other cases. MMF was introduced between 3 months and 36 months (13.5 +/- 7 months) after recurrence of the primitive glomerulonephritis. During combined MMF/cyclosporine/prednisone therapy, only 3 patients responded to MMF. MMF was disrupted precociously in 1 out of 3 patients who stabilized renal function because of discovery of lung cancer and in 2 out of the 3 other patients because of gastrointestinal intolerance and severe anemia. We supposed that MMF could represent a new effective alternative therapy of recurrent glomerulonephritis on renal graft in some cases.

We have investigated the metabolic effects of segmental (neoprene-injected) pancreas transplantation versus whole (enteric-diverted) pancreas transplantation. Seventeen uremic insulin-dependent diabetes mellitus (IDDM) patients received a simultaneous pancreaticorenal transplant: in a prospective, randomized study, 9 patients received a segmental neoprene-injected graft (group A) while 8 patients received a total pancreatico-duodenal graft, with enteric diversion (group B). The immunosuppressive therapy was based on ALG, CsA, azathioprine, and steroids. Three months after surgery, patients were submitted to the following metabolic investigation: i.v. and oral glucose tolerance tests, Hba 1, i.v. arginine test, and a 24-hr metabolic profile. The OGTT, HbA1, and metabolic profile were repeated 12 and 24 months after transplantation. At 3 months after transplantation, the OGTT showed delayed insulin secretion and higher blood glucose levels in group A. Serum insulin levels after IVGTT or arginine were higher in group B than in group A. OGTT at 12 and 24 months were unchanged in group B, while in group A a higher incidence of impaired glucose tolerance (IGT) and diabetes mellitus response were observed. HbA1 and blood glucose levels during the 24-hr profile showed good metabolic control in both groups at 3, 12, and 24 months. We can conclude that both the segmental and total pancreas transplantation restore a good metabolic control in IDDM patients, though a higher incidence of IGT and DM responses were observed after OGTT in the patients receiving a segmental graft. These abnormalities do not seem to interfere with metabolic control in everyday life. These results seem to be the consequence of the different B cell masses transplanted with these two techniques.

The successful development of fetal tissue transplantation has resulted in therapeutical solutions for patients with a variety of diseases. Fetal liver transplants as well as bone marrow transplants, can completely cure patients with severe combined immunodeficiency disease. These transplants can also be applied to treat other types of immunodeficiency, hemopathies, and inborn errors of metabolism, in association with immunosuppressive therapy. Despite complete HLA incompatibility between transplanted stem cells and host cells, functional activities of donor-derived T-lymphocytes are not restricted. In severe forms of Di George syndrome, immunological reconstitution can be obtained by fetal thymus transplantation. It is expected that, in the near future, pure stem cell transplants and gene transplants will develop and will provide remarkable solutions for the therapy of a large number of diseases.

Since many years our attention has been focused on the isolation of an immunosuppressive fraction from the serum of uremic patients. This fraction which was obtained after a single chromatography of uremic fluids on a Sephadex. G25 column, was shown to inhibit markedly the lymphocyte proliferation induced by several mitogens and by allogeneic cells. A continuous infusion of this material in rats allowed a significant prolongation of skin allograft survival. By contrast the antibody production to sheep red blood cells was not affected by such a treatment. Furthermore, this crude fraction reduced significantly the graft-versus-host reaction induced in lethally irradiated mice injected with allogeneic spleen lymphocytes previously incubated in the presence of the uremic factor. Inhibition of cell proliferation appears to be the common denominator of all these in vitro and in vivo immunosuppressive effects.

Despite absence of major modifications in the treatment of patients with a renal transplant, significant improvement, in terms of both patient and transplant survival, has been recorded over the last decade. Hopes that methods leading to the specific acceptance of the transplant by the host would be very shortly applicable in the clinic have not yet been fulfilled. More experience in the handling of previously available immunosuppressive drugs or procedures has, however, been associated with a decrease in the complication rate and a increase in transplant successes to a larger extent than usually anticipated (1, 2).

The therapeutic field of in utero transplantation of stem cells, into human fetuses, has developed since 1988 with the hope of improved probability of engraftment and tolerance, due to immune immaturity of the host. Fifteen years later, it is possible to evaluate the results that we and others have obtained in the treatment of several fetal diseases. Seven fetal patients have been treated in Lyon: In 2 cases, pregnancy termination was induced by the in utero injection; in the 5 other cases, engraftment was obtained and repeatedly documented with presence of donor HLA antigens and/or Y chromosome in recipients. In the 2 patients with combined immunodeficiency disease, a sustained reconstitution of immunity was obtained as a result of the transplant but other complications occurred thereafter. In patients with thalassemia major, Niemann-Pick disease or hemophilia, a very partial and very transitory benefit was only obtained. Approximately 33 other patients with immunodeficiencies, hemoglobinopathies or inborn errors of metabolism have been treated worldwide, over the last 13 years, with a comparable method, using parental or fetal stem cells transplanted in utero. Successful treatment has usually been recorded in immunodeficiencies, and insufficient results have been obtained in the other cases. This form of treatment can therefore be recommended after prenatal diagnosis of combined immunodeficiency but additional research is required to improve the degree of engraftment, the lack of resistance of the host and the ‘space’ available for hematopoiesis in the other conditions.

Fully HLA-mismatched stem cells from human fetal livers were transplanted into 17 infants and two fetuses to treat severe combined immunodeficiency disease in 1976-2000. Donor cell engraftment and immunological reconstitution were obtained in 14/ 19 patients, three of whom have been extensively and repeatedly studied immunologically during prolonged follow-up. T-cells were derived totally from donor cells; B-cells and antigen-presenting cells (APC) remained mainly of host origin. Due to class I and 11 mismatches between T-cells and all other cells (APC, B-cells, virus-infected target cells), limitations in the defense against infections in vivo and in T-cell functions in vitro (helper and cytotoxic activities) were predicted; however, these did not occur. Anti-tetanus toxoid responses (including specific antibody production) developed despite HLA disparities between T-cells and B-cells or APC in the chimeric children. Similarly, cytotoxic T-cells (of donor HLA phenotype) recognized host Epstein-Barr virus-infected target cells. Recognition of antigenic peptide by T-cells under these conditions involved presentation by host allogeneic HLA molecules and not by self HLA antigens. Tolerance to donor antigens was acquired by clonal deletion; tolerance to host antigens existed despite the presence of many host-reactive T-cells and involved clonal anergy.

FOLLOWING 19 years of experience in postnatal fetal liver transplantation (FLT), we have developed a new therapeutic method, namely the in utero transplantation of stem cells from the human fetal liver. This early transplant takes advantage of the immunological tolerance that exists in young fetal recipients. The six fetuses that we treated were 28, 26, 17, 14, and 12 weeks postfertilization. Three patients had immunodeficiencies, two others had thalassemia major and the last one had Niemann-Pick disease (type A). Donor cells were obtained from 7- to 13-week-old fetuses, with conditions approved by the National Committee for Bioethics. Donors and recipients were not matched. Under ultrasonic visualization, the fetal cells were infused through the umbilical vein of four patients and injected intraperitoneally into the 2 other ones. The first patient, born in 1988, has evidence of engraftment (T lymphocytes of donor origin expressing donor HLA specificities, in the host peripheral blood) and reconstitution of cell-mediated immunity. This child, who had bare lymphocyte syndrome,1 has no clinical manifestation of the disease and lives normally at home. The second child was born in 1989; donor cell engraftment has been proven (distinct HLA phenotype) and the severe immunodeficiency has been corrected to a large degree. One fetus with chronic granulomatous disease developed fatal bradycardia after a second in utero FLT. One fetal patient with thalassemia major had cardiac arrest following the intravenous infusion. The fifth patient, transplanted intraperitoneally at 12 weeks of fetal age, to treat thalassemia major, has evidence of donor cell take (Y chromosome in a female patient) and a partial effect on thalassemia has been obtained (HbA increased up to 30%, 1 year after birth); the proportion of donor versus host cells however tended to decrease over the following years suggesting that, in contrast with immunodeficient patients, thalassemic patients exhibit a selective advantage for the development of host, rather than donor, stem cells. The last patient treated by in utero FLT had Niemann-Pick disease. Engraftment was again obtained (donor HLA phenotype) but due to either the limited number of donor cells or the blood-brain barrier, moderate clinical and metabolic effects were seen, especially in the CNS. In all four patients who were born, no side-effect developed in the mother nor in the fetus. Several advantages appear to be associated with in utero FLT2: increased probability of graft take with development of specific immunological tolerance, ideal isolation of patient (in the uterus), and optimal environment for fetal cell development (in the fetal host). Immunological tolerance, in T cells deriving from donor stem cells, after education within host thymus, was shown to involve clonal deletion for donor antigens (deletion induced by donor dendritic cells and macrophages), and clonal anergy for host antigens (anergy induced by host thymic epithelial cells).3 High IL-10 production persisted for many years and was likely to play a role in the stable chimerism and tolerance maintenance.2

The aim of this study was to investigate a possible reenhancement of islet cell autoimmunity in type I (insulin-dependent) diabetic patients who received HLA-mismatched pancreas transplants from cadaveric donors and who underwent generalized immunosuppression. Circulating islet cell antibodies (ICA) and complement-fixing ICAs (CF-ICAs) have been tested at 1, 2, 3, 6, and 12 mo and at least once a year posttransplantation in 23 recipients of 25 transplants (22 simultaneous with kidney, 2 retransplants, 1 isolated; 23 segmentai neoprene injected, 2 whole with enteric drainage). Patients were aged 35.3 ± 1.9 yr with a duration of diabetes of 20.6 ±1.1 yr. Immunosuppression consisted of double or triple association of azathioprine, cyclosporin, and prednisone with or without temporary antilymphocyte globulins. The number of HLA-A and HLA-B compatibilities was none in 8 patients, one in 12 patients, two in 4 patients, and three in 1 patient. The mean follow-up was 4.0 ± 0.4 yr/patient (range 0.4–7.2). ICAs were positive pretransplantation in 2 of 25 patients and reappeared 1–42 mo posttransplantation in another 7. In 6 patients, CF-ICAs were also positive. In 7 of 9 ICA+ patients the pancreas transplant failed; in 1 patient this occurred 4 mo before ICA reappearance, and in 6 patients it occurred 2–35 mo after the first detection of ICAs. Pancreas-transplant failure was significantly associated with the positivity for ICAs (P < .05) and particularly for CF-ICAs (P < .005). ICA positivity was transitory in 4 patients (2–27 mo) and persistent in the remaining 5 (up to 61 mo). These findings suggest a possible reenhancement of islet cell autoimmunity in type I diabetic patients after HLA-mismatched pancreas transplantation, which could contribute to some cases of transplant failure.