B Cells in Transplantation of Rat, Mouse, and Man

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Fifty-five years ago, progress at several forefronts of immunology brought what seemed an epiphany that shaped the field of immunology for decades that followed. A search of longstanding for the anatomic origin of immunity had shown lymphocytes to be the cellular source of adaptive immunity, but the source of lymphocytes was uncertain until Bruce Glick found that eradication of the bursa of Fabricius in newly hatched chickens blocked production of antibodies (1957) and Jacques Miller found that surgical removal of the thymus in newborn mice temporarily prevented rejection of skin allografts (1961). Whether these organs or their equivalents functioned in series or in parallel and whether functions seen in one species would apply to others and especially to people was not clear. An answer to the first question came quickly when Szenberg and Warner in Melbourne (1962) and Cooper and Good in Minneapolis (1966) found that the bursa and thymus generate functionally distinct lymphocytes, the former producing antibodies and the latter mediating graft-versus-host reactions and graft rejection. This anatomic and functional dichotomy led to the division of immunology into humoral immunity investigated by B cell people and cellular immunity by T cell people, a segregation that persists despite the discoveries that the protein products of the “immune response” genes that govern Ab production actually do so by presenting antigen to T cells that in turn “help” and regulate antibody responses, that T cell-antigen-receptor diversification in the thymus and periphery depends on diversification of immunoglobulin, and that the development of lymphoid tissues needed for T cells to encounter antigens and the regulation of T cell responses depend on B cells.1 However, which unifying observations in mouse and other species can be applied in people remains unclear.
A new model system reported by Panzer and colleagues2 might help to address that question and, in doing so, help to reformulate lymphocyte biology. Panzer and colleagues asked whether and how B cells contribute to the early events after organ transplantation and did so using a new rat model rather than using established mouse models. Unmanipulated B cell–deficient mice reject organ allografts as quickly as wild type (WT) mice3,4; however, transplants in B cell– and T cell–deficient mice have far less ischemia-reperfusion and early dysfunction thought to be caused by natural antibodies and complement.5 To pursue this query further, the authors performed kidney transplants in B cell–deficient and WT rats and compared the function and pathology of kidney allografts on the seventh postoperative day.
The gene-targeted rats were probably not fully B cell deficient because targeting of mu heavy-chain exons does not preclude generation of some B cells capable of producing IgG or IgA (and indeed some IgG-producing cells were detected by enzyme-linked immunospot). However, the presence of some B cells probably allowed lymphoid organogenesis and T cell development to occur,1 without which some might question whether absence of B cells or aberrant T cells could explain whatever differences in outcome. Three clear and compelling findings emerged.
All transplants, 6 in WT and 5 in B cell–deficient rats, exhibited substantial early dysfunction. Transplants in WT rats had C4d deposits and more interstitial inflammation; B cell–deficient rats had increased expression of IL-10 mRNA in the spleen. Whether the early C4d and inflammation in WT and IL-10 in mutant rats will be found to presage rejection or absence thereof at later times remains to be seen; however, clearly none of these differences had an impact on graft function during the first week after transplantation.
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