Gamma‐globulin modulates growth of EBV‐derived B‐cell tumors in scid mice reconstituted with human lymphocytes

Abstract

The effect of weekly gamma-globulin injection on the development of human B-cell tumors was studied in 120 mice with severe combined immunodeficiency (SCID). The mice were injected intraperitoneally (i.p.) with human peripheral mononuclear cells (PBMC) from 6 different Epstein-Barr virus (EBV)-seropositive donors. Animals repopulated with cells from 5 donors received gamma-globulin or saline for 20 weeks and were followed up to 24 weeks after reconstitution. A delay in the appearance of fata EBV-derived human B-cell tumors was noticed in the gamma-globulin-treated groups as compared to the controls. In a separate experiment, the effect of gamma-globulin treatment during the initial 4 weeks after reconstitution was compared to treatment from week 5 to week 8 as well as to a continuous 20-week treatment. The results from this experiment showed that B-cell tumor growth could be prevented just as efficiently when the animals were treated only during the first 4 weeks. In contrast, no preventive effect was seen when the first gamma-globulin dose was given at the beginning of week 5 after reconstitution. Our results indicate that gamma-globulin reduces the frequency of EBV-derived B-cell tumor development and suggest that SCID mice repopulated with human cells represent a useful in vivo model for evaluation of the prophylactic and/or therapeutic effects of immunomodulatory treatments in lympho-proliferative disorders associated with immunosuppression.

A 16-Year Multi-Institutional Study of the Role of Age and EBV Status on PTLD Incidence Among Pediatric Heart Transplant Recipients

“…It is generally believed that cytotoxic T cells provide the main defense against symptomatic EBV infection and proliferation of EBV‐infected memory B cells (21). It is of interest to note, however, that anti‐EBV antibodies and human immunoglobulin preparations (which contain anti‐EBV antibodies) have been implicated as protective against PTLD in mouse SCID models (22,23), high viral loads in humans (24), and possibly against development of EBV infection/PTLD in pediatric and adult solid organ allograft recipients (16,25,26). Given that IVIG is occasionally used for treatment of EBV or CMV infections, it is possible that these treatments could influence the detection of anti‐EBV antibodies.…”

Human Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes home preferentially to and induce selective regressions of autologous EBV-induced B cell lymphoproliferations in xenografted C.B-17 scid/scid mice.

“…As originally demonstrated by Mosier et al (20), and confirmed in this and other reports (22,23,25), SCID mice inoculated with PBL from EBV-seropositive donors or with human EBV-transformed B cell lines rapidly develop lethal human EBV-induced lymphoproliferations with characteristics similar to those arising in immunocomproraised patients. Recently, several groups have used this preclinical model to explore the potential of gamma globulin (30), mAbs directed against human CD21, CD23, CD24, and CD40 B cell antigens (31)(32)(33), low dose IL-2 treatment (34), and imexon (35) in the treatment of human EBV-induced lymphoproliferations developing in the SCID mouse.…”

Preventive effect of IgG from EBV-seropositive donors on the development of human lympho-proliferative disease in SCID mice

“…With regard to LMPs, it has been shown that these molecules are mainly cytoplasmic ; but at least LMP1 spans the plasma membrane (Hennessy et al, 1984), and antibodies to this antigen could be functionally important. LMP1 also has been implicated in apoptotic events protecting EBV-infected cells from cell death by up-regulating expression of the cellular oncogene bcl-2 (Henderson et al, 1991), and low levels of anti-LMP1 antibodies were previously found in gammaglobulin preparations (Abedi et al, 1993). It is also possible that a mixture of antibodies against antigens belonging to the latent and replicative forms of EBV, present in gammaglobulin preparations, are necessary for prevention of tumor formation; therefore, examination of the therapeutic effect of antibodies against single antigens would be of great importance.…”

“…One donor was used on 2 occasions for PBMC donation. Donor selection was based on previous experiments using his PBMCs for reconstitution of SCID mice, which resulted in a complete prevention of EBV-derived human B-cell tumors following gammaglobulin treatment (Abedi et al, 1993). On both occasions, all SCID mice (n 5 163) were injected i.p.…”

“…There have been reports of an anti-tumor effect of anti-human B-cell monoclonal antibodies (MAbs) administered to SCID mice reconstituted with human B-cell lines (Durandy et al, 1992;Ghetie et al, 1992). We have shown previously that treatment with human gammaglobulin may inhibit the formation of B-cell tumors in SCID mice without interfering with the engraftment of human cells in repopulated animals (Abedi et al, 1993). Since gammaglobulin preparations are pools of IgG prepared from the plasma of a large number of donors, most of whom are EBV-seropositive, they contain a variety of antibodies against EBV-related antigens.…”