BEYOND HYPERACUTE REJECTION - ACCELERATED REJECTION IN A DISCORDANT XENOGRAFT MODEL BY ADOPTIVE TRANSFER OF SPECIFIC CELL SUBSETS

If hyperacute rejection is prevented in the guinea-pig (GP)-to-Lewis r at (Lew) cardiac xenograft (CXg) model, an accelerated rejection invol ving cellular infiltration occurs in 3 to 4 days, In previous work usi ng an adoptive transfer model, we found that this accelerated rejectio n was facilitated by either sensitized splenocytes or sensitized serum , In the current study, in an attempt to determine which splenocyte su bset(s) facilitated this process, sensitized splenocytes, with or with out subset depletion were injected, into complement- and natural antib ody-depleted Lew recipients of GP CXgs. Graft survival was 4.18 +/- 0. 75 days with no injection (n = 11), 4.13 +/- 0.99 days with naive sple nocytes (n = 8), 1.80 +/- 0.45 days with sensitized splenocytes (n = 5 ), 2.67 +/- 1.03 days with CD4(W3/25(+)) depletion of the sensitized s plenocytes (n = 6), 3.13 +/- 0.84 days with CD8(OX8(+)) cell depletion (n = 8), 4.70 +/- 0.68 days with macrophage depletion (n = 10), and 4 .22 +/- 0.41 days with B cell depletion (n = 9). Cellular infiltrates, hemorrhage, myocyte necrosis, and endothelial deposition of IgG, IgM, and fibrin were seen in rejected grafts, In most groups, infiltrating cells consisted of CD4 (W3/25(+)), CD8 (OX8(+)), IL2R(+) cells, macro phages, and natural killer (NK) cells. However, in the macrophages-dep leted group, activated (ED2(+)) macrophages and NK cells were signific antly reduced. Total IgM, anti-GP IgM, and anti-GP IgG rebounded in al l groups over several days but were not consistent at the time of reje ction. Lewis rats rejecting GP CXgs early had lower final titers than those rejecting later. Total IBG titers rebounded to baseline by postt ransplant day 1 and were therefore similar in all groups at the time o f rejection, These findings suggest that this accelerated rejection re quires interaction between macrophages and B cells, since depletion of either significantly alters the rejection tempo. A possible explanati on is that xenoreactive IgG antibodies, synthesized by sensitized B ce lls, bind their target antigens - but also bind sensitized macrophages through their Fc region, thus causing rejection by antibody-dependent cell-mediated cytotoxicity.