Shoji Koga

Long-term results of ABO-incompatible living kidney transplantation: a single-center experience.

Background. Despite great efforts to promote the donation of cadaveric organs, the number of organ transplantations in Japan is not increasing and a serious shortage of cadaveric organs exists. These circumstances have forced a widening of indications for kidney transplantation. For this purpose, ABO-incompatible living kidney transplantations (LKTs) have been performed. Although we have already reported the short-term results of ABO-incompatible LKT, there is no report of long-term results in such cases; anti-A and anti-B antibodies could cause antibody-induced chronic rejection and result in poor long-term graft survival. In this study, we have reviewed the long-term results of ABO-incompatible LKT and tried to identify the most important factors for long-term renal function in ABO-incompatible LKT. Methods. Sixty-seven patients with end-stage renal failure underwent ABO-incompatible living kidney transplantation at our institute between January, 1989, and December, 1995. The mean age was 34.9 years (range, 8-58 years), with 38 males and 29 females. Incompatibility in ABO blood group antigens was as follows: A1<O, 23 patients; B→O, 19 patients; A1B→A1, 7 patients; B→A1, 8 patients; A1→B; 4 patients; A1B<B, 4 patients; A1B→O, 2 patients. The number of HLA-AB, and -DR mismatches were 1.6±1.1 and 0.76±0.6, respectively. Plasmapheresis and immunoadsorption were carried out to remove the anti-AB antibodies before the kidney transplantation. In the induction phase, methylprednisolone, cyclosporine, azathioprine, antilymphocyte globulin, and deoxyspergualin were used for immunosuppression. Local irradiation of the graft was performed at a dose of 150 rad, on the first, third, and fifth days after transplantation. Splenectomy was done at the time of kidney transplantation in all cases. Results. Patient survival was 93% at 1 year and 91% at 8 years. Graft survival was 79% at 1, 2, 3, and 4 years, 75% at 5 and 6 years, and 73% at 7 and 8 years. Patient survival was not significantly different from that of ABO-compatible patients. However, graft survival was significantly different between ABO-incompatible grafts and ABO-compatible grafts. Specifically, ABO-incompatible transplant recipients experienced a significantly higher rate of early graft loss up to 3 years but showed an equivalent graft loss by year 4. Among 67 patients, 16 grafts were lost during the observation period. Loss was due to acute rejection in 5 patients, followed by chronic rejection in 5 patients and death with function in 3 patients, whereas immunosuppression was withdrawn in 3 patients due to nonimmunological reasons. Of 16 grafts lost, 15 were lost within 1 year after transplantation. Of the 67 patients, 5 died during observation. Three patients with functioning grafts died of uncontrolled bleeding due to duodenal ulcer, malignant lymphoma, and cerebral hemorrhage (one patient each). One patient died of ischemic colitis due to secondary amyloidosis and one patient of cerebral hemorrhage after graft loss due to humoral rejection. There was no fatal infectious complication, whereas 10 patients had non-tissue-invasive cytomegalovirus infection. The stepwise logistic regression model was employed to identify the most important factors for long-term renal function.

Early expression of interferon-gamma inducible protein 10 and monokine induced by interferon-gamma in cardiac allografts is mediated by CD8+ T cells.

BACKGROUND Our goal was to test the intragraft mRNA expression and production of two chemokines that are potent chemoattractants for antigen-primed T cells, interferon-gamma inducible protein 10 (IP-10) and monokine-induced by IFN-gamma, (Mig), in allogeneic heart grafts. METHODS Syngeneic or allogeneic A/J (H-2a) hearts were heterotopically transplanted to wild-type, CD4-/-, CD8alpha-/-, or IFN-gamma-/- C57BL/6 (H-2b) recipients. To test expression of IP-10 and Mig, grafts were removed 1-8 days posttransplant for RNA isolation and Northern blot analysis. To test the potential recipient leukocyte populations mediating intraallograft expression of IP-10 and Mig, recipients were treated with anti-NK 1.1, anti-CD4, and/or anti-CD8 monoclonal antibodies before transplantation. RESULTS Allogeneic heart grafts transplanted to wild-type, but not IFN-gamma-/-, recipients expressed IP-10 and Mig at day +2 posttransplant that increased thereafter until rejection was completed. Expression of IP-10 and Mig in isografts was low or undetectable. Cardiac allografts from CD8+ T cell depleted, but not NK cell or CD4+ T cell depleted, recipients had low to undetectable expression of IP-10 and Mig on day +2 posttransplant. Similarly, cardiac allografts from CD8-/-, but not CD4-/-, recipients had low to undetectable expression of IP-10 and Mig on day +2 posttransplant. CONCLUSIONS Early intraallograft expression of Mig and IP-10 during primary rejection of cardiac allografts is dependent on the activities of recipient CD8+ T cells.

Intraallograft Chemokine RNA and Protein During Rejection of MHC-Matched/Multiple Minor Histocompatibility-Disparate Skin Grafts

Chemokines direct leukocyte recruitment into sites of tissue inflammation and may facilitate recruitment of leukocytes into allografts following transplantation. Although the expression of chemokines during rejection of MHC-disparate allografts has been examined, chemokine expression in MHC-matched/multiple minor histocompatibility Ag-disparate allografts has not been tested. The intraallograft RNA expression of several C-X-C and C-C chemokines was tested during rejection of full thickness skin grafts from B10.D2 donors on control Ig-, anti-CD4 mAb-, and anti-CD8 mAb-treated BALB/c recipients. In all recipients, two patterns of intragraft chemokine expression were observed during rejection of these grafts: 1) macrophage-inflammatory protein-1α, macrophage-inflammatory protein-1β, GRO-α (KC), JE, and IFN-γ-inducible protein (IP-10) were expressed at equivalent levels in allo- and isografts for 2–4 days posttransplant and then returned to low or undetectable levels; and 2) IP-10 and monokine induced by IFN-γ (Mig) were expressed in the allografts 3 days before rejection was completed, suggesting a possible role in recruiting primed T cells into the allograft. Three days before completion of rejection, intraallograft IP-10 protein was restricted to the epidermis, whereas Mig was located in the lower dermis and associated with the intense infiltration of mononuclear cells. Treatment of B10.D2 recipients with rabbit antiserum to Mig, but not to IP-10, delayed rejection of the allografts 3–4 days. The results suggest that Mig mediates optimal recruitment of T cells into MHC-matched/multiple minor histocompatibility Ag-disparate allografts during rejection.

T-cell mediated induction of allogeneic endothelial cell chemokine expression.

Background. The goal of the current study was to test the ability of T cells to stimulate allogeneic endothelial cells to express chemokines, particularly the T-cell recruiting factors monokine induced by interferon-&ggr; (Mig) and inducible protein (IP)-10. Methods. Lymph node cells from C57BL/6 (H-2b) recipients of C3H (H-2k) skin grafts or from naïve mice were added to monolayers of C3H-derived endothelial cell line 2F-2B. After 5 or 24 hr, the lymph node cells were removed, and RNA was prepared from the endothelial cells and tested by ribonuclease protection assay or Northern blot hybridization for endothelial cell expression of chemokines. Results. Alloantigen-primed T cells induced endothelial cell expression of regulated on activation normal T-cell expressed and secreted (RANTES), IP-10, Mig, monocyte chemotactic protein-1, macrophage inflammatory protein-1&agr;, and macrophage inflammatory protein-1&bgr; within 5 hr of coculture. In vitro chemotaxis assays demonstrated the production of T-cell chemoattractants by the endothelial cells. With the exception of low levels of monocyte chemotactic protein-1 and RANTES, culture with naïve C57BL/6 lymph node T cells did not induce endothelial cell chemokine expression. Alloantigen-primed CD4+ T cells induced endothelial expression of IP-10 and RANTES but none of the other chemokines tested, whereas primed CD8+ T cells induced all of the chemokines tested. Expression of IP-10 and Mig was not induced when alloantigen-primed T cells from interferon-&ggr; deficient recipients of C3H skin grafts were cultured with the endothelial cells. This expression was blocked by addition of intercellular adhesion molecule-1 or lymphocyte function-associated antigen-1 specific antibodies to the cultures. Conclusions. These results demonstrate the ability of alloantigen-primed CD8+ T cells to quickly and directly stimulate endothelial cells to express and produce chemokines, including those recruiting T cells.

CD8+ T cells produce RANTES during acute rejection of murine allogeneic skin grafts.

Background. Based on their chemoattractant properties, it is likely that chemokines play a role in recruiting alloantigen-primed T cells to allografts and in amplifying inflammation within the graft. The graft-infiltrating leukocytes producing specific chemokines remain largely unknown. Methods. We tested the intragraft RNA expression of the chemokine RANTES (regulated on activation normal T expressed and secreted) and granzyme B during rejection of full thickness, allogeneic skin grafts by C57BL/6 mice. Grafts with different immunogenetic disparities were chosen to test expression when rejection was mediated by CD4 + , CD8 + , or both CD4 + and CD8 + T cells. RNA expression was also tested in purified CD4 + and CD8 + T cell populations from skin graft recipients. Immunohistology was performed on graft sections to test colocalization of RANTES protein and graft-infiltrating CD4 + and CD8 + T cells. Results. Intra-allograft RANTES RNA expression was not observed during CD4 + T cell-mediated rejection. Expression of RANTES and granzyme B RNA was observed at low levels in purified populations of CD8 + , but not CD4 + , T cells from the spleen and lymph nodes of graft recipients beginning at day 7 after transplantation and increased thereafter. Intra-allograft RANTES protein was associated with a small number of graft-infiltrating CD8 + T cells but was also associated with endothelial cells and with many graft-infiltrating CD4 + T cells. Conclusions. CD8 + T cells produce RANTES during allogeneic skin graft rejection. In the allograft, the chemokine also colocalizes with CD4 + T cells that do not produce RANTES.

Safety and efficacy of docetaxel, estramustine phosphate and hydrocortisone in hormone-refractory prostate cancer patients

Objective:  To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone‐refractory prostate cancer (HRPC).

A case of rapid progressive glomerulonephritis with IgA deposits after renal transplantation.

Shimizu T, Tanabe K, Tokumoto T, Shimmura H, Koga S, Ishikawa N, Oshima T, Toma H, Yamaguchi Y. A case of rapid progressive glomerulonephritis with IgA deposits after renal transplantation. Clin Transplantation 2001: 15 (Supplement 5): 11–15. ©Munksgaard, 2001

A case of acute antidonor antibody-mediated humoral rejection after renal transplantation with specific consideration of serial graft biopsy histology

Abstract: A 61‐year‐old‐woman with end‐stage renal disease caused by IgA nephropathy received living unrelated kidney transplantation from her husband in February 2001. Pre‐transplant donor‐specific T‐ and B‐cell cross‐match was negative. Immunosuppressive treatment consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), methylprednisolone (MP) and antilymphocyte globulin (ALG). The kidney functioned immediately after kidney transplantation. On post‐operative day 9, the level of serum creatinine (S‐Cr) rose from 1.1 to 1.5 mg/dL. The allograft biopsy specimen taken on the day revealed moderate accumulations of polymorphonuclear leucocytes in peritubular capillaries (PTCs), dilatation of PTCs and transplant glomerulitis, moderate to severe. Immunofluorescent study of a frozen section of the allograft biopsy specimen showed a strong, diffusely distributed endothelial staining pattern in PTCs for the stable complement split product C4d. Post‐transplant donor‐specific T‐ and B‐cell cross‐matches performed on post‐operative day 13 were positive. From the allograft biopsy and the positive post‐transplant donor‐specific T‐ and B‐cell cross‐matching, acute humoral rejection (AHR) associated with the development of antidonor antibodies (ADA) was diagnosed. Plasma exchange (PE) treatment was initiated on day 11. After a total of 13 treatments of PE, donor‐specific T‐ and B‐cell cross‐matches became negative and the biopsy performed on day 72 revealed mild transplant glomerulopathy without accumulation of polymorphonuclear leucocytes in PTCs or a C4d staining pattern in PTCs of immunofluorescence. The allograft functioned well and the creatinine level was 1.1 mg/dL 7 months post‐transplant. This was a case of AHR after renal transplantation associated with the development of ADA, which was triggered by spousal‐donor antigens. The presence of widespread C4d deposition in PTCs in renal allograft biopsies played a role in the diagnosis of AHR and the diagnosis was confirmed by positive donor‐specific T‐ and B‐cell cross‐matches at the time of rejection, which were negative at pre‐transplantation. Several treatments of PE were effective for resolving AHR in this case and the effect of PE in the treatment of AHR could be assessed by the degree of peritubular capillaritis (PTCitis) and C4d deposits in PTCs.

Effects of direct injection of dehydrated ethanol on PC3 human prostate cancer cells in nude mice: Preliminary study

Objectives:  The effect of direct local injection of dehydrated ethanol on hormone‐independent prostatic carcinoma cells (PC3 cells) implanted in nude mice was investigated.