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PubMed1984

Covalent binding efficiency of the third and fourth complement proteins in relation to pH, nucleophilicity, and availability of hydroxyl groups.

The binding of [3H]glycerol and [3H]putrescine to C3 was studied in a fluid-phase system using trypsin as the C3 convertase. The binding of glycerol showed little variation in the pH range between 6.0 and 10.0. The binding of putrescine (pKa = 9.0) is rather ineffective below pH 7.5 but becomes more efficient as the pH of the reaction mixture increases. These results agree with the contention that the final step of the binding reaction is the transfer of the acyl group of the exposed thio ester of C3 to a nucleophile since the nucleophilicity of hydroxyl groups is rather independent of pH whereas only the unprotonated form of amino groups is nucleophilic. The inefficient reaction of amino groups with the exposed thio ester of C3 is also supported by the study of the inhibitory activity of serine and its two derivatives, N-acetylserine and O-methylserine, to the binding of [3H]glycerol to C3. N-Acetylserine showed an inhibitory activity equivalent to that of serine, whereas O-methylated serine showed only minimal activity. It can be concluded, therefore, that serine reacts with the thio ester of C3 by its hydroxyl group but not by its alpha-amino group. The ability of the alcohol group of various alkanes to inhibit the binding of [3H]glycerol to C3 was also studied. The primary alcohols inhibit the binding reaction with an efficiency that is similar to glycerol, and there are no significant differences in the binding efficiencies of methanol, ethanol, 1-propanol, and 1-butanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗
PubMed2002

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

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.

Antibodies↗
PubMed2003

C4d deposition in peritubular capillary and alloantibody in the allografted kidney suffering severe acute rejection.

BACKGROUND: Alloantibodies and C4d deposition in peritubular capillaries (PTCs) are thought to be related to antibody-mediated acute rejection. The purpose of this study was to evaluate the relationship between C4d deposition in PTCs and alloantibodies at various days after allograft dysfunction due to severe acute rejection. METHOD: There were 620 renal transplantations (Tx) performed. Forty patients diagnosed with acute humoral and/or vascular rejection showed graft dysfunction with anuria or dysuria. The patients were divided into four groups by ABO compatibility and clinical course after graft dysfunction: compatible recipients with graft loss (c-GL; n = 6); compatible recipients with recovery from graft dysfunction (c-RE; n = 10); incompatible recipients with graft loss (i-GL; n = 9); and incompatible recipients with recovery from graft dysfunction (i-RE; n = 15). RESULTS: C4d depositions in 4/6 c-GL recipients increased, and those in 8/10 c-RE recipients decreased after graft dysfunction. These changes in C4d deposition between the c-GL and the c-RE groups were significantly different (P < 0.01). These titres of anti-A/B IgG antibody in 7/9 i-GL recipients increased and those in 8/15 i-RE recipients decreased after graft dysfunction. These changes in titre between the i-GL and the i-RE groups were significantly different (P < 0.01). All c-GL recipients and 4/10 c-RE recipients had anti-HLA antibody at the last biopsy. There was a significant difference in the number of recipients who had anti-HLA antibody between the c-GL and the c-RE groups (P < 0.05). CONCLUSIONS: These results indicate that changes in C4d deposition in PTCs in the c-ABO group and titre of anti-A/B IgG antibody in the ABO-incompatible groups exert a strong impact on graft survival after dysfunction in the early period after Tx.

ABO Blood-Group System↗
PubMed2003

C4d deposition in the glomeruli and peritubular capillaries associated with transplant glomerulopathy.

Transplant glomerulopathy (TGP) is a unique disease entity with characteristic pathological findings. Although ultrastructural studies for TGP have been performed, histogenesis of TGP is not fully understood. The present study was designed to investigate the relation of complement fragment C4d to the histogenesis of TGP. Nine cases of isolated TGP were randomly selected. A commercially available monoclonal antibody against complement fragment C4d was used in allograft biopsies. To evaluate the extent and severity of deposition of the C4d complement in the glomerular and peritubular capillaries, indirect immunofluoresce method was performed on frozen sections. Intense deposition of C4d in the glomerular basement membrane and peritubular capillaries was found in association with morphological appearance of TGP. Peritubular capillaries were affected in all the patients, showing splitting and multilayering of peritubular capillary basement membrane. These changes, which diffusely affect most capillaries, and their severity pattern were quite similar in each patient. In early stages of all patients with cellular rejection, C4d was not detected in the glomerular and peritubular capillaries. In addition, no C4d deposition was detected in all zero-hour biopsies without diagnostic abnormality. These findings suggest that C4d deposition in the glomerular and peritubular capillaries might be associated with the pathogenesis of TGP in renal transplantation.

Adult↗
PubMed2000

Complement activation reaches maximum during equilibrium between antigen and antibody in an in vitro model for thrombolysis with streptokinase.

Treatment with streptokinase (SK) of patients with acute myocardial infarction (AMI) is known to activate the complement system. In a previous investigation we found a great variation in the degree of complement activation taking place during infusion of SK in patients with AMI (range: 0-293% increase in pretreatment complement split product 3d (C3d) levels). In this in vitro study we added SK to serum with different concentrations of SK-antibodies (SK-Ab) and found that both the relative concentrations and the total concentrations of SK and Ab determined the degree of complement activation elicited by SK. This finding was in accordance with the Kendall-Heidelberger equation of antigen-antibody equivalence. Furthermore, we found parallel rises in C3d and C4d, indicating that complement was activated via the classical pathway. A condition for maximal complement activation is antigen-antibody equivalence.

Antigen-Antibody Reactions↗
PubMed2003

Use of C4d as a diagnostic adjunct in lung allograft biopsies.

PURPOSE: Humoral allograft rejection is a defined mechanism for cardiac and renal graft dysfunction; C4d deposition, a stable component of complement activation, inversely correlates with graft survival. With the recent recognition of humoral rejection in lung grafts, we examined C4d's role as a prognostic adjunct in lung allografts. MATERIAL AND METHODS: Twenty-three lung recipients underwent biopsies for deterioration in clinical status or routine surveillance. Clinically unwell patients possessed acute rejection or bronchiolitis obliterans syndrome (BOS). Biopsies attributable to infection were excluded from the study. In addition to routine light microscopy, an attempt was made to correlate the clinical status and morphologic findings with the pattern of C4d deposition and also to compare these clinical and morphologic parameters with the other assessed immunoreactants. Panel reactive antibody testing was also carried out at various points in their post transplantation course whereby in 6 of the cases the samples were procured at exactly the same time as the tissue samples. RESULTS: The patients were segregated into two groups: those patients with recurrent acute rejection and those with BOS. In those patients with symptomatic acute rejection, all biopsies showed light microscopic and immunofluorescent evidence of humoral allograft rejection. The level of C4d was positively correlated with the degree of parenchymal injury, the hallmark being one of septal capillary necrosis. In addition, high and intermediate levels of C4d correlated with a clinical diagnosis of acute rejection. C4d was the strongest predictor of parenchymal injury and of the clinical status (p <.0001) compared to other the immunoreactants C1q, C5b-9 and immunoglobulin. There was no specific correlation between C4d deposition and the presence of acute cellular rejection. In those patients fulfilling clinical criteria of BOS, deposits of C4d as well as other immunoreactants were found in the bronchial wall as opposed to the rarity of this finding in bon-BOS patients. However the only statistically significant predictor of BOS was bronchial wall deposition of C1q. In no case were panel reactive antibodies at significant levels discovered post transplantation. CONCLUSIONS: In the context of acute rejection, C4d deposition correlates with clinical evidence of rejection and the degree of humoral rejection assessed pathologically; there is no association with the presence of histocompatibility related antibodies. It is a more specific predictor of allograft status compared to other immunoreactants. C4d deposition within the bronchial wall is a feature of BOS and hence may be used as a marker of chronic graft dysfunction. The antigenic target resulting in C4d deposition may not be histocompatibility related.

Adult↗
PubMed2003

Association of humoral immunity and bronchiolitis obliterans syndrome.

Animal studies have shown that blockade of complement may reduce the severity of and/or prevent the development of bronchiolitis obliterans syndrome (BOS), suggesting a role for complement activation. We explored the hypothesis that humoral immunity plays a role in the evolution of BOS. Thirteen unilateral lung transplant patients with BOS defined the patient population. Fresh frozen tissue was analyzed for deposition of C1q, C4d, C5b-9 and immunoglobulin (IgG, IgM, IgA). An indirect immunofluorescent assay was also conducted with patient serum against cytospins of the pulmonary endothelium. In each case the biopsies showed a microvascular injury syndrome involving the bronchial wall characterized by one or more of hemorrhage, fibrin deposition, and endothelial cell necrosis. Other features included bronchial epithelial and chondrocyte necrosis. The end-stage lesion was a thinned bronchial epithelial lining mural fibrosis. Immunofluorescent analysis showed deposition of C1q, C3, C4d, C5b-9, and immunoglobulin in the bronchial epithelium, chondrocytes, basement membrane zone of the bronchial epithelium, and bronchial wall microvasculature. The indirect antiendothelial cell antibody assay was positive in all tested. Humoral immunity may play a role in the pathogenesis of BOS; the antigenic targets include the bronchial wall microvasculature, bronchial epithelium, and chondrocytes.

Aged↗
PubMed2003

Complement C4d in graft capillaries -- the missing link in the recognition of humoral alloreactivity.

Staining of C4d in graft capillaries has emerged as a useful method to detect antibody-mediated rejections in situ. Demonstration of capillary C4d has provided substantial clinical results and allows several conclusions: Antidonor antibodies (preformed or produced de novo) activate complement directly in the graft. Capillary C4d is present in about 30% of biopsies with acute and chronic rejections and separates rejections with a humoral component from 'pure' cell-mediated rejections. Recognition of humoral alloreactivity is important, since effective treatment is now available. Since capillary C4d can appear and disappear at any time post transplantation, every transplant biopsy should be tested. Capillary C4d is now incorporated in the 'Banff classification'. The incidence of C4d-positive cases will probably decline because of the 'routine' application of potent immunosuppressants, including mycophenolate mofetil, that can inhibit antibody production. Presensitization, however, will remain a potential threat to allografts.

Animals↗
PubMed1993

Capillary deposition of C4d complement fragment and early renal graft loss.

Clinical outcome of kidney grafts that are affected by the complex syndrome of 'early graft dysfunction' is uncertain and rather unpredictable. In this study, an individual prognosis for dysfunctioning allografts (N = 93) is attempted by the immunohistological assessment of vascular classical complement activation in graft biopsies. Thus, capillary deposition of complement fragment C4d was observed in the majority (N = 51) of early dysfunctioning grafts. In 43 biopsies, abundant deposition of fragment C4d was present in all capillaries, whereas in eight specimens a segmental distribution of capillary C4d was observed. In 42 grafts with early dysfunction no capillary C4d was detectable. Eighteen subsequent graft losses within one year (16 early losses) were recorded in the subgroup with C4d in all capillaries, and three early losses in the group with segmentally distributed C4d. Only four graft losses (3 early losses) were recorded in the C4d-negative group (P = 0.0027; Pearson's chi square test). The resulting one-year graft survival rates (72% for the study group) differed markedly between the subgroups. Grafts with generalized or segmental capillary deposition of C4d had 57% and 63% survival, respectively, contrasted by 90% survival in the C4d-negative group. It is of note, however, that also three of the four grafts that were finally lost within the C4d-negative group, showed distinct capillary deposition of C4d in second biopsies. Vascular deposition of complement fragment C4d therefore represents a clinically relevant factor that contributes to early graft dysfunction. Its assessment is helpful for an individual graft prognosis.

Animals↗
PubMed2004

Acute rejection and graft survival in renal transplanted patients with viral diseases.

Transplanted patients are susceptible to viral infections; thus, the aim of this study was to evaluate the features of acute rejections and the outcome of the renal graft in transplanted patients with herpes virus diseases. Renal biopsies from 30 renal transplanted patients undergoing early acute rejection (type IA and IB according to the Banff 97 classification) were evaluated. In total, 15 of these patients experienced cytomegalovirus (CMV) or Epstein-Barr virus disease within the first year following transplantation (group I) and 15 patients showed no evidence of viral infection (group II). No significant differences between the groups in terms of age, male/female ratio, living/cadaveric donor ratio, cold ischemia time, HLA A-B matching, pretransplant panel reactive antibody test, occurrence of post-transplant tubular necrosis, plasma levels of cyclosporin A and mean percent increase of serum creatinine at the time of the biopsy were observed. In group I biopsies, the mean number of interstitial plasma cells, as well as the mean number of CD79a-positive cells (B lymphocytes and plasma cells) was significantly higher than in group II (P<0.01 and <0.01, respectively). There was a positive correlation between the number of infections and the number of plasma cells (P<0.05). In transplanted patients, CMV can trigger the formation of anti-endothelial cell antibodies, which have been proposed to play a role in antibody-mediated rejections. We investigated whether a deposition of C4d, a marker of antibody-mediated reactions, was present in renal peritubular capillaries. In group I C4d deposition was found in five cases, while in group II it was not observed (P<0.05). In group I, 7/15 patients developed chronic allograft nephropathy vs 1/15 patients in group II (P<0.05). The estimated 1-, 5- and 8-year cumulative graft survival rates were 80, 66 and 57%, respectively, in group I, while in group II the estimated 8-year cumulative survival rate was 100% (P<0.05). In conclusion, acute rejection biopsies of patients with viral infections displayed plasma cell infiltrates and, in several cases, C4d deposition. Our study suggests a role of B lymphocytes in the pathology of these rejections and confirms the association between viral infections and poor graft survival.

Adult↗
PubMed1986

Detection of disulphide bonds and localization of interchain linkages in the third (C3) and the fourth (C4) components of human complement.

Disulphide bonds contribute significantly to the maintenance of structural/functional integrity of many proteins. Therefore it was of interest to study the distribution and the effect of disulphides on conformation of complement components C3 and C4. These proteins are precursors of several fragments with various binding sites and distinct physiological functions. The constituents of C3c (beta, alpha 27, alpha 43) and those of C4c (beta, alpha 27, alpha 16, gamma) were investigated, since other fragments of C3 or C4 do not participate in interchain linkages. Inter-and intra-chain disulphide bonds in C3c and C4c were localized by using a modification of conventional SDS (sodium dodecyl sulphate)/polyacrylamide-gel electrophoresis such that the change in mobility of disulphide-bond-containing proteins can be detected throughout the transition from a non-reduced to a fully reduced state. Several forms of the alpha 43 fragment from C3, and of the gamma-chain of C4, with different mobilities can exist, depending on the number of intra-chain disulphide bonds reduced. The intermediates (heterodimers) generated by a partial reduction of C3c or C4c were characterized by two-dimensional SDS/polyacrylamide-gel electrophoresis performed in the absence, then in the presence, of beta-mercaptoethanol. The inter-chain linkages in C3c were determined to be beta-alpha 27 and alpha 27- alpha 43, thus indicating the presence of only one interchain bond in C3. The two interchain bonds in C4c are beta-alpha 27 and alpha 16-gamma. The third interchain bond in C4 (alpha 27-gamma, tentative) remains to be determined.

Complement C3↗
PubMed2001

Complement activation plays a key role in the side-effects of rituximab treatment.

Treatment with rituximab, a chimaeric anti-CD20 monoclonal antibody, can be associated with moderate to severe first-dose side-effects, notably in patients with high numbers of circulating tumour cells. The aim of this study was to elucidate the mechanism of these side-effects. At multiple early time points during the first infusion of rituximab, complement activation products (C3b/c and C4b/c) and cytokines [tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6) and IL-8] were measured in five relapsed low-grade non-Hodgkin's lymphoma (NHL) patients. Infusion of rituximab induced rapid complement activation, preceding the release of TNF-alpha, IL-6 and IL-8. Although the study group was small, the level of complement activation appeared to be correlated both with the number of circulating B cells prior to the infusion (r = 0.85; P = 0.07) and with the severity of the side-effects. We conclude that complement plays a pivotal role in the pathogenesis of side-effects of rituximab treatment. As complement activation can not be prevented by corticosteroids, it might be relevant to study the possible role of complement inhibitors during the first administration of rituximab.

Adult↗
PubMed1998

Immunoglobulin prolongs survival of pig kidneys perfused ex vivo with human blood.

Intravenous immunoglobulin (IVIG) (Octagam), was used to determine the effect on hyperacute rejection in an ex vivo xenograft model. Six pig kidneys were perfused with IVIG and fresh human AB blood, and six control pig kidneys were simultaneously perfused with albumin and blood from the same donation. The survival of the IVIG-perfused xenografts (median, 6.5 h) was significantly (P = 0.03) longer than the albumin-perfused xenografts (median, 3.5 h). Complement was activated in both groups. The administration of IVIG to the perfused blood resulted in immediate and significantly higher complement activation in the fluid phase as compared with the albumin group. At rejection the fluid phase complement activation was higher in the IVIG group than in the albumin group for C1rs/C1inh complexes, C4bc, Bb and TCC. At the time of rejection both the albumin and the IVIG group demonstrated interstitial tubular haemorrhage, vasculitis or necrosis of glomerular capillaries and glomerular microthrombi. IgM, C1q, C3c, C4 and fibrin were located in arteries and glomeruli and IgG in the interstitium in both groups at rejection. The fluid phase findings are consistent with a modulatory effect of IVIG on complement activation by deviating the classical pathway activation towards the fluid phase. The prolonged survival of the IVIG-perfused kidneys suggests that IVIG may be useful to dampen hyperacute rejection.

Animals↗
PubMed2001

Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts.

BACKGROUND: The contribution of humoral alloreactivity to the rejection of renal allografts is not well defined because humoral antigraft reactions are not easily detectable in transplant biopsies, and serial measurements of circulating allo-antibodies in the post-transplantation period are not routinely performed. We have developed diagnostic techniques that improve the assessment of humoral alloreactivity in vivo and in vitro. METHODS: Humoral alloreactivity in transplant biopsies derived from 218 single kidney grafts was detected by assessing the deposition of complement fragment C4d in interstitial capillaries. Circulating alloantibodies were determined in corresponding serum samples by flow cytometry using lymphoblastoid cell lines of donor DR-type as target cells and by a conventional microcytotoxicity test. The impact of capillary C4d and other selected variables on renal graft survival was calculated by univariate and multivariate analysis. RESULTS: Capillary C4d, present in 46% of biopsies from first grafts and 72% of regrafts, is related to circulating alloantibodies. Grafts with capillary C4d have a markedly shorter survival than grafts without capillary C4d (50% graft survival, 4 vs. 8 years, P = 0.0001). Among several risk factors, capillary C4d is the strongest predictor of subsequent graft loss in a multivariate analysis (relative risk, 2.1, 95% CI, 1.4 to 3.1). Humoral alloreactivity detectable within six months after transplantation has a much stronger impact on graft survival than alloreactivity detected beyond this period. CONCLUSIONS: Humoral alloreactivity, manifested by the capillary deposition of complement C4d in about 50% of biopsied renal grafts, exerts a strong impact on graft survival when it operates within six months after transplantation.

Adult↗
PubMed2003

Monocytes and peritubular capillary C4d deposition in acute renal allograft rejection.

BACKGROUND: Peritubular capillary (PTC) deposition of complement split factor C4d in renal allografts has been shown to be closely associated with circulating antidonor antibodies and a marker for relatively poor graft survival. Monocyte/macrophage (MO) infiltration of renal allografts has been shown to adversely affect graft survival. The purpose of this study was to assess whether the two phenomena are related. METHODS: Twenty-three biopsies (from 15 patients) demonstrated diffuse strong staining of PTC for C4d (C4d+ group) and acute tubular injury with or without significant cellular rejection, while 28 biopsies (with acute rejection) but negative for PTC C4d served as controls (C4d- group). RESULTS: The C4d+ group demonstrated significantly greater glomerular and interstitial MO infiltration than did the C4d- group [3.4 +/- 2.0 vs. 0.2 +/- 0.3 MO/glomerulus, P < 0.0001; 12.9 +/- 9.2 vs. 6.5 +/- 5.0 MO/high power field (hpf), P = 0.0030]. Neutrophilic (PMN) infiltration of glomeruli and PTC was also significantly greater in the C4d+ group than in the C4d- one (0.8 +/- 0.6 vs. 0.3 +/- 0.3 PMN/glomerulus, P = 0.0003; 0.9 +/- 0.8 vs. 0.4 +/- 0.3 PTC PMN/hpf, P = 0.0035). CONCLUSION: The results indicate a close association between PTC C4d deposition and MO infiltration, particularly glomerular, and confirm previous observations regarding the correlation of PTC C4d staining and PMN infiltration.

Acute Disease↗
PubMed2003

Plasmapheresis in C4d-positive acute humoral rejection following kidney transplantation: a review of 4 cases.

Acute and chronic rejection after kidney transplantation has long been exclusively attributed to cellular and vascular mechanisms. Modern immunosuppressive therapy, therefore, addresses the cellular immune system. Rising experiences in kidney transplantation in the last few decades have revealed that some types of rejection are refractory to the conventional immunosuppressive treatment. Humoral rejection. which has previously been reported as a crucial factor in hyperacute rejection, is now suspected to play also an important role in acute and chronic rejection. Acute humoral rejection (AHR) is characterized by immunohistochemical detection of C4d deposits in peritubular capillaries. As shown for other antibody-mediated diseases, such as some autoimmune diseases, plasmapheresis has been suggested to be an efficient therapeutic approach in AHR. We present four patients with C4d-positive AHR in the early phase after kidney transplantation. In three of the four patients, humoral graft rejection was successfully treated by plasmapheresis. Graft function was significantly improved with a stable long-term outcome. One patient lost the graft. Although the number of patients with C4d-positive AHR treated by plasmapheresis is limited, plasma exchange appears to be an efficient and powerful therapeutic approach to control humoral rejection.

Acute Disease↗