Prevention of Murine Cardiac Allograft Rejection With Gallium Nitrate

Abstract

Gallium nitrate (GN) was evaluated for its ability to interfere with a cute rejection of DBA/2-->C57BL/6 heterotopic cardiac allografts, in comparison with the depleting anti-CD4 mAb, GK1.5. The administration of GN for 30 days (s.c. 30 mg/kg elemental gallium on days 0 and 3, 10 mg/kg every third day) resulted in >60-day graft survival in 78% (25 of 32) of the graft recipients, whereas 2 perioperative injections of anti-CD4 monoclonal antibody (mAb) resulted in >60-day graft survival in 58% (24 of 41) of the graft recipients. Serum gallium levels peaked at about 2000 ng/ml after 2-3 weeks of treatment and decreased to about 300 ng/ml by day 60, a level that was maintained for at least 30 more days. During the early posttransplant period, 25% of GN-treated grafts, but not anti-CD4 mAb-treated grafts, exhibited an unusual, transient reduction in graft impulse strength, suggesting a transient rejection response. Macroscopically, the long-surviving (>60 days) grafts from either treatment group exhibited none of the features of rejecting allografts. Histologically, they exhibited minor edema and rare epicardial inflammation but no tissue necrosis. However, there were vascular changes in allografts from GN-treated mice, including altered endothelial morphology, associated with moderate intimal hyperplasia and mild perivascular leukocytic infiltration. Allografts from anti-CD4 mAb-treated mice exhibited prominent neointimal hyperplasia associated with endothelial morphologic changes and prominent vascular and perivascular leukocytic infiltration. In general, both GN and anti-CD4 mAb promoted long-term allograft survival, but these allografts displayed the histopathologic signs of ongoing inflammation and chronic allograft rejection.

Murine Renal Allografts: Spontaneous Acceptance Is Associated with Regulated T Cell-Mediated Immunity

“…This was followed by 28 days of continuous delivery via osmotic minipumps (model 2002, Alzet, Palo Alto, CA), which delivered 0.5 l (12.5 g GN)/h. Circulating levels of GN fall to subtherapeutic levels within 7 days of pump removal (10).…”

“…Interestingly, some of these agents can be withdrawn after a relatively brief period of peritransplant treatment with minimal risk for the subsequent development of acute rejection. Such agents include anti-VCAM-1 mAb (7), anti-CD4 mAb (8), anti-CD40 ligand (anti-CD40L) mAb (9), and gallium nitrate (GN) 3 (10). Many investigators have studied the immunobiology of this phenomenon, but the specific mechanisms by which these agents subvert acute rejection and promote allograft survival after treatment is discontinued remain ill defined.…”

Evaluation of immune regulation in transplant patients using the trans vivo delayed type hypersensitivity assay

“…This archetypical pro-inflammatory T cell response is indicative of prior proinflammatory allosensitization. However, if allograft recipients are transiently treated with various immunosuppressisve agents, graft acceptance is achieved (5), and the recipients fail to display DTH responses when challenged with donor alloantigen (6).…”

Donor IFN-γ Receptors Are Critical for Acute CD4+ T Cell-Mediated Cardiac Allograft Rejection

“…The dependence upon CD4 T cells for acute rejection of cardiac allografts is most clearly illustrated by the absence of acute rejection in CD4 knockout hosts (1) or following anti-CD4 mAb therapy (1)(2)(3)(4)(5)(6). CD4 T cells do not merely serve a helper role in the response, in that purified CD4 T cells are also sufficient, in the absence of CD8 cells or B cells, to mediate rejection of vascularized cardiac allografts (6,7).…”