The vascular bed as the primary target in the destruction of skin grafts by antiserum. II. Loss of sensitivity to antiserum in long-term xenografts of skin.

Abstract

Rat skin that survives for long periods of time on immunosuppressed mice becomes resistant to anti-graft serum and remains so for as long as it survives. When long-standing grafts are removed and placed on new immunosuppressed mice, they remain resistant to antiserum for as long as they survive. The acquired resistance to antiserum seems, therefore, to be due to changes in the grafts rather than to changes in their hosts. Furthermore, it was found that the acquisition of resistance is correlated with replacement of graft endothelium by host cells, as demonstrated by the use of immunofluorescent techniques in conjunction with mouse anti-rat serum and rat anti-mouse serum. Evidently, humoral antibodies are able to cause acute damage to skin grafts, and presumably to grafts to other organized tissues, only if they react with antigens of graft endothelium. Long-term grafts that are retransplanted to their original donors or to rats syngeneic with those donors are in most cases rejected, whereas 14-d-old grafts similarly regrafted are in no case rejected. Apparently, the responses of the secondary recipients to the mouse endothelial antigens in long-term grafts lead to destruction of the entire grafts. When long-standing rat skin xenografts are removed and placed on untreated mice syngeneic with the primary hosts, they are in every case rejected, although they survive slightly longer than skin taken directly from rat donors. Rejection is accompanied by a mononuclear infiltrate and is qualitatively indistinguishable from the rejection of freshly prepared rat skin. Clearly, sensitized cells are more efficient than humoral antibody in destroying grafted tissues.

Monokine Induced by Interferon-γ (MIG/CXCL9) Is Derived from Both Donor and Recipient Sources during Rejection of Class II Major Histocompatibility Complex Disparate Skin Allografts

“…During rejection of Mig-deficient skin allografts, the chemokine protein was clearly present in the vascular endothelium of the lower dermis and was associated with cells around the vessels. These results are consistent with the neovascularization of the skin allograft by recipient endothelium [23][24][25] and the importance of this source of Mig in directing T-cell infiltration into the allograft. In contrast, Mig protein was not detected in vascular structures in the upper dermal vascular plexus of Mig Ϫ/Ϫ allografts and there was little to no detectable T-cell infiltration into this area of the allograft until late in the delayed rejection of the grafts.…”

The vascular bed as the primary target in the destruction of skin grafts by antiserum. I. Resistance of freshly placed xenografts of skin to antiserum

“…Free grafts of skin, unlike primarily vascularized grafts, do not have vascular connections with their hosts until about the 4th d after transplantation, a point that is affirmed by our studies with fluorescein-labeled antibodies. It would not be possible, therefore, to induce immediate vascular injury in recently placed grafts, and the induction of vascular injury seems to be a sine qua non of antiserum-mediated destruction of organized tissue grafts (4). This explains the resistance of grafts for the 1st 4 d after transplantation, but even after grafts are vascularized they remain resistant to antiserum for an additional 2 or 3 d and peak sensitivity is not acquired until about the 12th or 14th d after grafting.…”

Tolerance, Mixed Chimerism, and Chronic Transplant Arteriopathy

“…34). It may also be relevant that long-term surviving skin grafts can undergo gradual replacement of endothelial cells in small vessels by recipient-derived cells (35), whereas replacement of endothelial cells in transplanted organs is usually limited (36), although some reports suggest it to be present in varying degrees (37,38). On the other hand, considerable evidence now supports the view that the derivation of the majority of neointimal cells, bearing ␣-actin markers characteristic of smooth muscle cells, is from the recipient, although their origin, in different situations, may be either from bone marrow (39,40) or from adjacent vessel walls (41).…”