F. Fändrich¹, J. Schröder¹, T. Jahnke¹, A.M. Waaga³, M.R. Pawaresch², H.H. Wacker²

¹Dept. of General & Thoracic Surgery and ²Institute of Pathology, University of Kiel, Germany.
³Brigham and Women's Hospital, Harvard Medical School, Boston, MA, U.S.A.

Received 12/2/96; Accepted 12/18/96; On-line 01/01/97

DISCUSSION

Various studies have emphasized the rapid mutual exchange of donor and recipient lymphocytes between graft and host lymphatic tissues following small bowel transplantation (14). In the experimental setting of a GvH-model, donor lymphocytes are activated in the environment of the recipient's lymphatic organs (central sensitization), whereas host lymphocytes stimulate an allospecific anti-host immune response after migration to the lymphatic tissues of the graft, namely, lamina propria and Peyer's patches of the small bowel and adjacent mesenteric lymph nodes (peripheral sensitization) (15).

The observed pattern of sequential proliferation of host- and donor-derived sinus lining cells, and then by follicular dendritic cells sheds new light on the firm correlation between bone marrow derived sinus lining cells and follicular dendritic cells. The origin of FDCs is still strongly debated, as earlier studies identified this cell entity to belong to the reticular cell type derived locally from primitive reticular cells or from mesenchymal cells (pericytes around capillaries) (16,17). Experiments by Humphrey et al. (16) who investigated bone marrow chimeras demonstrated that FDCs were of host origin, thus supporting the notation of a reticular dendritic cell type. In contrast, Pawaresch et al. (18), Wacker et al. (1), and Szakal et al. (2,3) have demonstrated cells with a follicular dendritic phenotype in human, rat, and mouse blood, respectively. From their experiments, it was concluded that follicular dendritic cells may originate from blood cells derived from bone marrow. Kapasi et al. clearly provided support for the bone marrow as being a source of FDC precursors by the use of SCID mouse-rat and SCID-mouse F1 chimeras (19).

In line with findings by Szakal et al. (2,3) for the mouse species, Wacker has demonstrated for the rat a similar dendritic cell type of monocyte origin by the use of autoradiographic labeling studies (1). This dendritic cell was designated, sinus lining cell, as it was mainly localized in the subcapsular sinus floor where one of its functions was envisioned to mediate antigen trapping and presentation. Migration of SLCs to the follicle cortex was postulated, since SLCs could be traced in the follicle center by the use of electron microscopy.

The findings in this paper give direct evidence that a specific immunogenic stimulus leads to activation of SLCs in host mesenteric lymph nodes within the first 72 hours after reperfusion of the grafted organ. The fact that host-derived SLCs were activated by donor-derived immunocompetent cells entering the afferent vessels of the recipient's mesenteric lymph nodes can be assumed for the following reasons: host-derived (F1) immunocompetent cells which circulate through the graft will be recognized as non-self and will give rise to a specific anti-host response by graft-derived effector cells. Conversely, these circulating host lymphocytes and monocytes will not recognize graft cells as non-self as they carry one half of the parental genome themselves. Moreover, activated passenger leukocytes released by the graft enter the host lymphatic tissues and elicit a direct anti-host immune response. The apparently immunogeneic character of the observed proliferation and migration pattern of the host-derived SLCs is strengthend by the fact that syngeneic grafts did not trigger an activation and did not reveal an increase of the number of SLCs in the host lymphatic organs. For these reasons, it is justified to conclude that activation of the SLCs within host lymphatic organs was due to the interaction of invading graft-derived cells or graft-derived soluble antigens. In this context, it is noteworthy that the graft-associated immune attack against the host tissues simultaneously induced an activation and proliferation of the immunocompetent dendritic cells of the host's immune arm.

Whereas 15-deoxyspergualin warranted a mutual and sustained antigen exchange between activated DCs in the graft and within the host, progression of the graft-versus-host reaction led to a substantial damage of certain GvH-related target organs, such as spleen, lymph nodes, liver, skin, small bowel, and thymus. Thus, a second step of host tissue destruction ensued the initial activating stimululs. However, 15-deoxyspergualin immunosuppression effectively inhibited the GvH-mediated injury to B and T cell compartments of the secondary lymphatic organs and conferred a permanent activation of B cell follicles with consecutive formation of germinal centers, which was not observed in the non-immunosuppressed animals.

B cell proliferation, differentiation, and affinity maturation has been linked to an intact interaction between virginal B cells and the specific effector cells of the activated (secondary) follicles, such as centrocytes, centroblasts and FDCs. As soon as immunogenic antigens invade the body, specific antibodies against these antigens are formed which give rise to antigen-antibody complexes. Most of these immune complexes are ingested by the mononuclear phagocytes. A small part, however, will be trapped on the surfaces of cell processes protruding from the follicular dendritic cells (20,21). It has been emphasized that these FDC-immobilized antigen-antibody complexes play a crucial role in the generation of memory B cells (21) and in the phenomenon of "affinity maturation" (22). It is worthwhile to mention, in this context, that antigen complexed with antibody can induce germinal centre proliferation of B cell memory without evoking a detectable antibody response (23). Petrasch et al. demonstrated that isolated FDCs appear to stimulate the proliferation of B-cells in vitro while suppressing immunoglobulin G (IgG) production at the same time (24). Taken together, there is now strong evidence, that the mechanism of antibody mediated generation of B-cell memory and "affinitiy maturation" on one side and the mechanism of enhancing antibody responses on the other side might well be orchestrated by two quite different pathways.

Immunosuppressed animals which keep the balance between donor and host specific antigen presentation mediated by specialized dendritic cells are prone to long-term survival and graft acceptance (25). SLC's and FDCs appear to sustain normal B-cell development within the lymphatic follicles, which in turn is necessary for an adequate humoral response and an efficient cell-mediated immunogeneic response via activation of CD4-helper T-cells within the T-cell dependent areas. Whether this balanced antigen presentation by specialized dendritic cells is the basis for the stable microchimerism following vascularized solid organ transplantation, as speculated by Starzl et al. (25), will be subject of further long-term investigations.