Interleukin-1 and Interleukin-2 Defects Associated With Murine Graft-Versus-Host-Induced Immunodeficiency

The grafting of cells from donors incompatible for non-H-2 antigens alone can lead to GvHR mortality in up to 100% of lethally irradiated adult recipients. GvHR severity correlates with the number of mature immunocompetent cells present in the bone marrow inoculum. Histologic and clinical manifestations of GvHR observed in these mice differ from those seen when GvHR is induced across an H-2 barrier. The number of non-H-2 genes capable of influencing GvHR mortality is probably great, and their effects may vary as a function of sex. The non-H-2 genes influence GvHR mortality mainly via their interactions, the consequences of which are complex and can result in either cumulative or suppressive effects. GvHR mortality is considerably reduced by donor immunization, shortly before grafting, against host-specific non-H-2 antigens; and it is virtually abrogated by an additional immunization of the donors against nonspecific (foreign) H-2 antigens. Three weeks after grafting, these "protected" mice are easily distinguishable from those undergoing lethal GvHR, as assessed by both clinical appearance and histologic examination; in contrast, they are nearly indistinguishable from control mice grafted with syngeneic cells. However, depending upon the conditions used for the immunization, an additional immunization against nonspecific H-2 antigens can lead to acceleration rather than suppression of GvHR mortality; this phenomenon is not seen, under the same experimental conditions, after immunization against specific non-H-2 antigens alone. It is therefore suggested that a "second signal" provided by an additional nonspecific stimulus can potentiate either the establishment of specific suppression or the activation of a secondary ("positive") response. Suppressive effects of the specific and nonspecific immunizations are cumulative, and both treatments activate suppressor cells. The intensity of suppression induced by both specific and nonspecific immunizations is antigen dose-dependent. At equivalent antigen doses the specific immunization is considerably more effective than the nonspecific immunization, and is detectable after injection of as few as 2.5 X 10(5) cells. In both cases, irradiation of the immunizing cells abolishes the suppression induced by the lower cell doses tested, while it merely decreases the intensity of the suppression induced by the higher cell doses tested. The impairment of suppression after irradiation of the immunizing cells is not attributable to a modification of their homing pattern, but to the fact that proliferation of the immunizing cells, which leads to an augmentation of the antigen dose, is abolished by irradiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Section: Immune Reactivity Of Recipients Grafted With Cells From Untrsupporting

confidence: 87%

Parameters Involved in the Induction and Abrogation of the Lethal Graft‐versus‐Host Reaction Directed against non‐H‐2 Antigens

Hallé-Pannenko

Pritchard

Bruley-Rosset

et al. 1985

“…In contrast, 86% of normal mice produced between 11 and 25 units of IL-2 and the remaining normal mice produced a minimum of 6 units of IL-2 ( Fig. 4) (Mendes et al 1985b). Additional studies have demonstrated that IL-2 production is also suppressed early during the active phase of suppression; however, the precise nature of the suppressor cell has not been delineated (Niven & Lapp 1984).…”

Section: Late Suppressive Events -Evidence For a Maturational Defectmentioning

confidence: 96%

The Functional and Histological Basis for Graft‐versus‐Host‐Induced Immunosuppression

Lapp

Ghayur

Mendes

et al. 1985

Self Cite

The GvH reaction resulting from the injection of parental strain cells into adult F1 hybrids suppresses both cell-mediated and humoral immune responses and is dependent on the donor-host combination and the number of parental cells used to induce the GvH reaction. The early suppression is due, at least in part, to the increased number of macrophages and the activation of suppressor macrophages which act directly on the T-helper cell and perhaps the B-cell as well. The macrophage suppression is associated with an increase in PGE production. The long-term T-cell immunodeficiency is mediated by GvH-induced thymic dysplasia resulting in a block or an arrest in T-cell differentiation and deficient IL-2 production. The B-cell immunodeficiency is associated with both a decrease in B-cell production from lymphoid progenitors and a decrease in CFU-s production. The GvH reaction induces 2 types of thymic lesion, a stress-related effect causing atrophy of the thymic cortex and a cytolytic process causing severe-to-moderate lesions in the thymic medulla as a consequence of injury to medullary epithelial cells and a loss of Hassall's corpuscles (thymic dysplasia). By employing the NK-cell-deficient beige mutation, it was shown that the severe-to-moderate thymic medullary lesions occurred in F1 mice only in those transplant situations in which the donor inoculum was of the +/bg genotype, regardless of the genotype of the recipient. It is proposed that activation of parental T cells may contribute to the early immunosuppressive events; however, the relatively permanent immunosuppression appears to be associated with NK-like effector cells which are capable of causing injury to lymphoid and epithelial tissue, especially epithelium of the thymic medulla. These studies raise the possibility that the GvH reaction may contribute to some T- and B-cell immunodeficiencies observed in the SCID and AIDS syndromes, as well as in patients following bone marrow transplantation.

“…The observations that inoculation of parental T lymphocytes into Fi hybrid mice can result in loss of function of the host's T cells raised the possibility that this defect would be associated with a loss of IL 2 production and/or IL 2 receptor expression. It has been previously reported that spleen cells from GvH mice are unable to make IL 2 (Mendes et al 1985). and that they do not express IL 2 receptors (Joseph et al 1985) under conditions which are optimal for the production of IL 2 and expression of IL 2 receptors, i.e., 48 h after stimulation with Concanavalin A (Con A).…”

Section: Loss Of Il 2 Production and Il 2 Receptor Expression In Gvhimentioning

confidence: 99%

Cellular Interactions in Graft‐versus‐Host‐Induced T cell Immune Deficiency

Moser

Iwasaki

Sherer

1985

The present review summarizes some of this laboratory's recent findings and interpretations concerning the cellular interaction involved in graft-versus-host-induced immune deficiency. Our results indicate that GvHID induced by parental T cell recognition of allogeneic F1 class I plus class II MHC determinants abrogates CTL responses involving both self + X and H-2 alloantigen recognition. In contrast, GvHID induced by parental T cell recognition of only allogeneic F1 class II antigens reduces self + X CTL responses, but does not reduce allogeneic CTL activity. Parental T cell recognition of only class I H-2 antigens does not affect CTL responses. The GvHID is associated with a loss of ability of spleen cells from GvH mice to produce IL 2 and to express IL 2 receptors after stimulation with T cell mitogens. This reduction in IL 2 potential is associated with a reduction in T cells that survive mitogenic stimulation in culture. Freshly explanted spleen cells from GvHID mice exhibit normal numbers of T cells. Our findings are discussed in terms of there being distinct helper T cell pathways for the generation of CTL to self + X and alloantigens (Singer et al. 1984). The model proposed for selective loss of self + X T cell immunity in class II-induced GvHID is discussed with respect to the parallel selective loss of self + X CTL activity in the developmental stages of acquired immune deficiency syndrome (AIDS).