Role of kupffer cells and suppressor T cells in the graft versus host reaction after intrahepatic lymphoid tissue implantation.

Semiallogeneic lymph nodes were implanted into the livers of rats to study the roles of Kupffer cells and suppressor T cells in immunosuppression during the graft versus host (GVH) reaction. Two experimental procedures have been used to impair the function of both types of cells separately, namely, blockade of phagocytosis by a colloidal substrate at the time of antigen recognition or adult thymectomy 10 weeks before the induction of the GVH reaction. The results suggest that a subpopulation of the recipient's short-lived T lymphocytes is involved in the immunosuppressive function of the intact liver. In contrast it appears that Kupffer cells are not an essential component of the protective mechanisms of the liver.     

Concomitant changes in adenylate cyclase and cytolytic activities of lymphoid cells during graft versus host reaction.

Spleen cells from adult F1 hybrid mice undergoing the graft versus host reaction due to the inoculation of lymphoid cells of parental origin showed increased adenylate cyclase activity and cytolytic activity. A time-course study revealed that both the adenylate cyclase and cytolytic activities started increasing at Day 4 and reached maximum at Day 8 of initiation of the graft versus host reaction. Furthermore, the magnitude of both adenylate cyclase activation and cytolytic activity were dependent upon the number of parental cells injected into the F1 hybrid recipients. Elevated adenylate cyclase activity was also observed in spleen cells from irradiated animals undergoing the graft versus host reaction in which the nonspecific, but not the specific cytolytic activity was markedly depressed.     

Acute graft versus host disease after orthotopic liver transplantation

ABSTRACT: Graft versus host disease (GVHD) is an uncommon complication after orthotopic liver transplantation (OLT) with an incidence of 0.1-2%, but an 80-100% mortality rate. Patients can present with skin rashes, diarrhea, and bone marrow aplasia between two to eight weeks after OLT. Diagnosis of GVHD is made based on clinical and histologic evidence, supported by chimerism studies showing donor HLA alleles in the recipient bone marrow or blood. Several therapeutic approaches have been used for the management of GVHD after OLT including increased immunosuppression, decreased immunosuppression, and cellular therapies. However, success rates have been low, and new approaches are needed.     

Immunosuppressive role of the liver in the graft versus host reaction]

The ability of the liver to reduce the intensity of the graft versus host (GVH) reaction has been investigated in F1 hybrid rats implanted with parental lymph nodes. Intrahepatic and intrarenal tissue implantations were compared using classical GVH criteria. The intrahepatic implantation of lymph nodes suppress the mortality observed after intrarenal implantation. The results confirm the interest of portal drainage in organ transplantation and suggest a new site of implantation for lymphoid cells.     

Complement in graft versus host disease: IL Depletion of complement components during a systemic graft versus host reaction in the rat (38499).

Serum complement (C) and C components were examined during a systemic graft versus host (GVH) reaction in the rat. In our series of experiments (Lewis times Brown Norway) F-1 hybrid rats (60-80g) were given 200 times 10-6 or 400 times 10-6 Lewis spleen cells intravenously. Clinical GVH disease appeared 5-7 days after cell injection. Five of six rats in the experimental groups had a fall in levels of serum C2 (20-76%) and C4 (75-98%). Only one of six rats in the control group had a significant fall in C components. In a subsequent experiment (Fisher 344 times Brown Norway) F-1hybrid rats (60g) were given 400 times 10-6 Fischer 344 spleen cells or 200 times 10-6 Fischer 344 Ficoll-Hypaque separated spleen lymphocytes. Clincal GVH disease in this instance appeared on day 10. As in the previous experiments C2 and C4 fell markedly, 20-60% and 60-8-%, respectively, from baseline titers. The control groups did not have a significant fall in C2 or C4. Further examination showed reduction in C3, C5, C6,AND C8 suggesting a sequential activation of the C system via the classical pathway. We have postulated that the cells undergoing blast transformation may be activating the C system through membrane changes during the GVH reaction. Furthermore, the deficiency of C AND C components during GVH disease may contribute to the increased susceptibility of the host to infection and sepsis.     

Participation of mouse T- and B-lymphocytes in the graft versus host reaction]

Cells of the spleen or lymph nodes of CBA mice were transplanted to sublethally irradiated (CBAXC57BL/6)F1 mice; this caused development of the graft-versus-host reaction (GVHR). Lymphocytes lost the capacity to realize this reaction after in vitro treatment with specific sera against mouse T- and B-lymphocytes. Apparently, development of the GVHR in mice was connected with the cooperative interaction of T- and B-lymphocytes.     

Immunosuppression and lymphoid hypoplasia associated with chronic graft versus host disease is dependent upon IFN-gamma production

We have previously shown that both IFN-gamma and IFN-beta are produced in vivo and in vitro by spleen cells obtained from mice experiencing a chronic form of graft vs host disease (GVHD). Further, we have shown that in vitro production of IFN-beta by spleen cells from GVHD mice may play a role in the suppressed in vitro mitogen responsiveness of these cells. This study was undertaken to investigate if treatment of such mice with mAb to IFN-gamma or IFN-beta could alter the immunosuppression or lymphoid hypoplasia associated with chronic GVHD. GVHD was induced across minor histocompatibilities by the i.v. injection of B10.D2 spleen cells into sublethally irradiated BALB/c mice. These mice were given daily injections for 20 days of one of the following: 1) mAb to IFN-gamma, 2) mAb to IFN-beta, or 3) control IgG. Histologic examination of these mice at 21 to 22 days post transplantation revealed that mice treated with mAb to IFN-beta or control IgG had dramatic hypoplasia of the thymus, spleen, and lymph nodes which was similar to untreated GVHD mice. Mice given mAb to IFN-gamma, however, had no lymphoid hypoplasia and had a near normal gross and histologic appearance of their thymus, spleen, and lymph node tissue when compared with syngeneic controls. In vitro mitogen-induced proliferative responses of spleen and lymph node cells obtained from GVHD mice or GVHD mice treated with mAb to IFN-beta were severely suppressed or absent. In contrast, spleen and lymph node cells from GVHD mice given mAb to IFN-gamma were capable of giving a significant in vitro proliferative response to Con A, PHA, and LPS. Further, natural suppressor cell activity and spontaneous production of IFN-beta, a characteristic of this form of GVHD, was absent in spleen cells obtained from GVHD mice treated with mAb to IFN-gamma. These results further identify the IFN as playing critical roles in the pathogenesis of GVHD.     

Characteristics of a xenogeneic lymphocyte transfer reaction: its use in the study of graft versus host capability of mouse lymphoid cells from various anatomic sites.

A xenogeneic intradermal lymphocyte transfer test is described in which mouse lymphoid cells from various anatomic compartments were injected intó guinea pigs. Murine peripheral blood lymphocytes and peritoneal exudate (mineral oil induced) cells gave significantly greater responses than did cells from the spleen or non-inflammatory peritoneal exudates. The “flare” reaction, characteristic of the allogeneic lymphocyte transfer test, was absent. Similar experiments conducted with presensitized donor cells produced a marked “flare” reaction, but only with blood and inflammatory exudate lymphocytes. The fact that the flare could be ablated by prior in vitro irradiation of donor cells suggests that the flare reaction is related, at least in part, to the mitosis of these cells in the host. Effects of host manipulations such as prior irradiation and decomplementation suggest that host factors may play a role in the expression of dermal inflammation. It is concluded that this particular xenogeneic transfer response varies with either; a) the number of effector cells in the transferate or; b) the differential ability of a given murine lymphoid population to survive in guinea pig skin or, to varying degrees, a combination of both.     

Effect of graft versus host reaction on cell cycle time in neonatal mouse jejunum

Abstract. The duration of cell cycle parameters in control mouse jejunum has been compared with that found following induction of a graft-versus-host reaction (GvHR) during the first 3 weeks of postnatal life.
Values for t_c , and t_G1 were found to decrease progressively during normal development: estimates for the whole crypt column in 21-day-old mice were approximately half to one quarter those found 6 days after birth 12.1 ± 0.5 hr and 24.2 ± 0.3 hr for t_c ; 2.8 ± 0.3 hr and 12.1 ± 0.3 hr for t_G1 respectively; (means ± SE). t_S and t_G2 were found to remain approximately constant during this period of neonatal development.
Injecting foreign spleen cells into 3-day-old mice produced no effect on crypt cell proliferation or cell cycle parameters measured 3 days later. GvHR mice studied 8 days after spleen cell injection, however, showed both an increase in crypt cell proliferation and decreases in the values for t_c and t_G1 , to levels similar to those normally found in 21-day-old control animals ( t_c 12.4 ± 0.4 hr and t_G1 5.4 ± 0.4 hr for 11-day-old GvHR mice). The possible mechanism leading to these changes is discussed.
The ability of GvHR to stimulate cell proliferation is used in the present work to test the hypothesis that the total number of cell divisions taking place after birth determines the temporal sequence of changes in disaccharidase content produced during neonatal development.     

Effect of graft versus host reaction on cell cycle time in neonatal mouse jejunum

The duration of cell cycle parameters in control mouse jejunum has been compared with that found following induction of a graft-versus-host reaction (GvHR) during the first 3 weeks of postnatal life. Values for tc and tG1 were found to decrease progressively during normal development: estimates for the whole crypt column in 21-day-old mice were approximately half to one quarter those found 6 days after birth 12.1 +/- 0.5 hr and 24.2 +/- 0.3 hr for tc; 2.8 +/- 0.3 hr and 12.1 +/- 0.3 hr for tG1 respectively; (means +/- SE). tS and tG2 were found to remain approximately constant during this period of neonatal development. Injecting foreign spleen cells into 3-day-old mice produced no effect on crypt cell proliferation or cell cycle parameters measured 3 days later. GvHR mice studied 8 days after spleen cell injection, however, showed both an increase in crypt cell proliferation and decreases in the values for tc and tG1 to levels similar to those normally found in 21-day-old control animals (tc 12.4 +/- 0.4 hr and tG1 5.4 +/- 0.4 hr for 11-day-old GvHR mice). The possible mechanism leading to these changes is discussed. The ability of GvHR to stimulate cell proliferation is used in the present work to test the hypothesis that the total number of cell divisions taking place after birth determines the temporal sequence of changes in disaccharidase content produced during neonatal development.     

Pertussis vaccine as an inducer of suppressor cells inhibiting the local graft versus host reaction

The formation of nonspecific suppressor cells inhibiting the development of the graft versus host (GvH) reaction is shown to occur in the spleen of CBA mice after the injection of pertussis vaccine. 2 splenocyte populations have been found to possess suppressing activity: one of them comprises the splenocytes sensitive to anti-theta serum, carrying no receptors to IgG and IgM on their surface and incapable of adherence to the plastic surface; the splenocytes in the other population adhere to the plastic surface. During incubation and in vitro contact with the allogenic cells of intact donors the suppressor splenocytes release soluble mediators capable of suppressing the GvH reaction.