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A J Matas

Publications and source records attributed to A J Matas.

At least 181 records · Page 10Linked to original sources
PubMed1993

Prolongation of cardiac xenograft survival by depletion of complement.

Complement (C) activation is thought to be critical for the hyperacute rejection of xenografts. We investigated the role of C in the rejection of discordant cardiac xenografts by studying outcome in recipients depleted of C, using a highly purified form of cobra venom factor (CVF) in both a small (guinea pig [GP]-to-rat) and large (pig-to-baboon) animal model. A single dose of 30 or 60 units CVF given i.v. to rats completely abrogated hemolytic C activity for up to 72 hr. The lack of hemolytic C activity correlated with nearly undetectable serum levels of C3. Doses of 30 U/kg daily or 60 U/kg every other day over a 7-day period sustained C depletion without morbidity or mortality. Rats receiving GP cardiac xenografts during CVF therapy had significantly prolonged xenograft survival (88 +/- 10 hr in CVF-treated rats vs. 18.6 +/- 7.2 min in control rats, P < 0.001). Rats that rejected GP xenografts at 4 days posttransplant had higher levels of anti-GP antibodies than control rats, without hemolytic C activity at rejection. This rise in xenoreactive Ig reflected an increase in circulating IgG and IgM against GP antigens recognized before transplantation. Histologic analysis of GP cardiac xenografts taken from CVF-treated rats revealed leukocyte and monocyte margination along blood vessels, beginning at 12 hr posttransplant. Progressive cell infiltration, interstitial hemorrhage, and necrosis were observed over the next 72 hr. Rejected GP xenografts showed diffuse deposition of IgM and fibrin within blood vessels but no evidence of C3 deposition. A nonspecific pattern of IgG deposition was noted. CVF was tested in baboons. Complete C depletion was achieved with a dose of 60 U/kg, and was not associated with any morbidity or mortality. Xenotransplantation of a pig heart was performed in one baboon receiving CVF, 60 U/kg/day, for 2 consecutive days. Xenograft survival was prolonged to 68 hr, compared with 90 +/- 30 min in control baboons. Lack of hemolytic activity was noted during engraftment and at rejection. Histology showed evidence of vascular rejection. Immunopathology showed diffuse deposition of IgM, fibrin, and C4, and absence of C3 or membrane attack complex. We conclude that highly purified CVF can achieve marked C depletion with minimal morbidity and no associated fatalities. CVF alone can significantly prolong discordant cardiac xenograft survival. In the GP-to-rat model, the improvement in graft survival achieved with CVF was better than with conventional immunosuppression or isolated acute antibody depletion.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Early versus late acute renal allograft rejection: impact on chronic rejection.

We studied the effect of acute renal allograft rejection and its timing on the development of chronic rejection and subsequent graft loss. Between January 1, 1987 and April 30, 1991, 424 patients at the University of Minnesota received a primary kidney transplant (minimum follow-up, 1 year). Patients were subdivided by donor source, presence or absence of acute rejection, and the timing of acute rejection onset (early, < or = 60 days vs. late, > 60 days post-transplant). For living donor (LD) transplant recipients (n = 219), the incidence of chronic rejection is 0.8% in those who had no acute rejection (n = 130), 20% in those with acute rejection < or = 60 days (n = 59) (P < 0.001 vs. no acute rejection), and 43% in those with acute rejection > 60 days (n = 30) (P < 0.001 vs. no acute rejection, P = 0.04 vs. early acute rejection). For cadaver (CAD) transplant recipients (n = 205), the incidence of chronic rejection is 0% in those who had no acute rejection (n = 109), 36% in those with acute rejection < or = 60 days (n = 69) (P < 0.001 vs. no acute rejection), and 63% in those with acute rejection > 60 days (n = 27) (P < 0.001 vs. no acute rejection, P = 0.03 vs. early acute rejection). For both LD and CAD recipients, no grafts have been lost to chronic rejection among those who did not first have at least 1 acute rejection episode. In contrast, 23 patients with acute rejection have had graft loss to chronic rejection. For both LD and CAD recipients, those with > 1 acute rejection episode had significantly more chronic rejection than those with only 1 rejection (P < 0.05). There was no significant difference in the incidence of chronic rejection based on whether the first acute rejection episode was steroid resistant or steroid responsive. We conclude that acute rejection is strongly related to the development of biopsy-proven chronic rejection and subsequent graft loss. Patients undergoing their first acute rejection episode > 60 days (vs. < or = 60 days) have an increased incidence of chronic rejection.

Acute Disease↗
PubMed1993

Evidence that improved late renal transplant outcome correlates with the development of in vitro donor antigen-specific hyporeactivity.

Previous studies suggest stable renal transplant recipients can have either prednisone (P) or cyclosporine withdrawn; however, 30% of these patients undergo rejection requiring reinstitution of P or CsA. Some patients return to baseline creatinine levels, while others either stabilize at a higher creatinine level or lose their graft. It would be ideal to establish immunologically based criteria for selecting patients who can be successfully withdrawn or tapered from immunosuppression. We have investigated the development of donor antigen-specific hyporeactivity by using donor cells and/or homozygous typing cells defining the HLA-Dw specificities of the donor cells as stimulator cells in the mixed lymphocyte culture (MLC) and comparing the pre- and posttransplant responses of peripheral blood mononuclear cells from 199 kidney transplant recipients. Of these, 27% of the haploidentical living-related donor and 25% of the cadaver recipients developed in vitro donor antigen-specific hyporeactivity. The LRD recipients who did so have lower mean creatinine levels at 6, 12, and 24 months posttransplant (1.3, 1.3, and 1.2, respectively) than those who remained responsive to the donor antigens (1.6, 1.7, and 1.8) (P < 0.05). However, no differences in the mean creatinine levels were observed between CAD recipients who developed donor antigen-specific hyporeactivity and those who remained responsive. Rejection episodes were common in all groups in the first 3 months posttransplant; however, recipients who developed donor antigen-specific hyporeactivity tended to experience fewer rejection episodes after 3 months posttransplant. The percentage of recipients who remained rejection-free after 3 months post-transplant was 95% for CAD recipients who developed donor antigen-specific hyporeactivity vs. 83% for those who remained responsive. Only 1 hyporesponsive recipient (0/15 LRD; 1/20 CAD) developed chronic rejection vs. 12 (5/41, LRD; 7/60, CAD) recipients who remained responsive. For those with graft function at 3 months (when hyporesponsiveness was first determined), the actuarial 36-month graft survival was higher in the hyporesponsive (92%, LRD; 94%, CAD) than in responsive groups (LRD, 76%; CAD, 91%). No differences in the degree of HLA-DR mismatching (MM) were observed for the LRD hyporesponsive (1.20 DR MM) vs. reactive (0.98 DR MM) groups or for the CAD hyporesponsive (1.35 DR MM) vs. reactive (1.30 DR MM) groups. Donor antigen-specific hyporeactivity could not be determined (UND) for 30 of the LRD recipients and 33 of the CAD recipients due to lack of mismatching for DR antigens (0.03 DR MM and 0.25 DR MM, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗
PubMed1993

The immunopathology of cardiac xenograft rejection in the guinea pig-to-rat model.

The mechanisms underlying rejection by rats of vascularized guinea pig xenografts have been controversial. The aim of this study was to define, using sequential immunopathologic analysis, the contributions of xenoreactive antibody, complement, and effector cells to the rejection of guinea pig cardiac xenografts by Lewis rats. In untreated recipients, hyperacute rejection of guinea pig cardiac xenografts occurred in 20 +/- 10.2 min and was characterized by focal endothelial deposition of IgM and by diffuse deposition of C3. IgG was not localized to endothelial surfaces, but was present in the same locations as albumin, suggesting that the accumulation of IgG might reflect nonspecific leakage of plasma proteins from blood vessels. No polymorphonuclear or monocytic infiltrate was observed. Depletion from rats of xenoreactive antibody to undetectable levels prolonged the survival of guinea pig cardiac xenografts, but did not prevent hyperacute rejection; the rejected xenografts contained deposits of C3 along the microvasculature but no deposits of IgM or IgG. No cellular infiltrate was observed. Depletion of complement with cobra venom factor prolonged the survival of xenografts up to 96 hr. Xenograft tissues from complement-depleted animals had diffuse deposits of IgM along the microvasculature, but no detectable deposits of C3 or IgG were noted. Graft tissues obtained at various times after transplantation into complement-depleted animals revealed cellular infiltrates consisting of granulocytes, monocytes, and lymphocytes, but few cells bearing an NK cell phenotype. Our findings are consistent with the concept that complement activation is essential for the hyperacute rejection of discordant xenografts, and that in this particular model complement activation can proceed without the involvement of antibody. However, our findings also suggest that xenoreactive antibody contributes to hyperacute rejection and, along with effector cells, contributes to the later rejection of a xenograft when hyperacute rejection has been averted. Finally, we show that when hyperacute rejection is avoided, a form of vascular rejection occurs in which certain of the pathologic features--i.e., interstitial hemorrhage, interstitial edema, and thrombosis--are very similar to those observed in hyperacute rejection. Whether this form of rejection is a delayed form of the process that leads to hyperacute rejection or a novel pathologic process of graft rejection has yet to be determined.

Animals↗
PubMed1993

Rapamycin: immunosuppression, hyporesponsiveness, and side effects in a porcine renal allograft model.

Rapamycin prolongs allograft survival and induces donor-specific tolerance in some small animal transplant models. Large animal studies, however, are limited. We studied rapamycin in a porcine renal allograft model. Donor-recipient combinations were chosen based on high response in pretransplant MLCs. Allografts were anastomosed to the aorta and vena cava and the native kidneys removed. There were 5 treatment groups: (a) no immunosuppression; (b) triple therapy (CsA, 1 mg/kg/day; AZA, 2-3 mg/kg/day; and PRED, 3-4 mg/kg/day); (c) rapamycin (0.75 mg/kg/day i.m.) in carboxymethylcellulose (CMC); (d) rapamycin (0.25 mg/kg/day i.m. in CMC); and (e) a vehicle (CMC) control. Serum creatinine levels were determined every other day. Most allografts were biopsied once a week. Immunosuppression was stopped after 30 days. Mean graft survival in nonimmunosuppressed recipients was 6.8 +/- 3.6 days. Mean graft survival in triple therapy recipients (n = 10) was 45.7 +/- 36 days vs. 59.6 +/- 11.4 days in rapamycin (0.25 mg/kg/day) recipients (n = 7) (P = 0.51). Both triple therapy and rapamycin improved renal allograft survival versus nonimmunosuppressed controls (P = 0.0025 and 0.001, respectively). Serum creatinine levels were significantly lower (P < 0.05) in rapamycin versus triple therapy recipients. We conclude that rapamycin is a potent immunosuppressant in a porcine renal allograft model and may avoid the elevated serum creatinine levels associated with CsA.

Animals↗