- Email: [email protected]
tumor rejection and GVH?
Mcd&l Hypothesu (1990) 32,63-65 0 Lonmtan Group UK Ltd 1990
Are B Lymphocytes Involved Rejection and GVH?
in Allograft/Tbmor
G. KRISHNAN Tissue-Typing
Laboratory,
Our Lady of Lourdes Medical Center, Camden,
NJ 08103, USA
Abstract - Several earlier observations by us and other investigators led us to propose a thesis that 6 lymphocytes, when activated by a virus, allo-antigen or bacterial protein would enter into effector arm of the immune response and cause allograft and tumor rejection or GVH-type of lesion in immunosuppressed animals. These effector cells may act directly in the process by contact with other cells or liberating cytokines. Such an hypothesis needs further support from experiments involving cancer and transplantation patients’ B cells.
Abbreviations
arm of the immune response.(l-5) Welsh et al (1) have demonstrated the existence of a cell with a B cell phenotype capable of lysing virus infected target cells in a 3h assay. Bersani et al (2) have reported the cytotoxic potential of a normal B-lymphoblastoid cell line by using actinomycin sensitive WEHIcells in 6h 51 Cr release assay. We (3, 4) showed that a normal B-lymphoblastoid cell line (RPMI-1788) caused GVH type of lesion in immunosuppressed rats, prolonged the survival of L-1210 tumor bearing DBA/2 mice by 3-5 days, released 51 Cr from 51 Cr K-562 cells in vitro and destroyed the human lung carcinoma cell line (A-549) in a monolayer flask. We (5) also showed that cancer mononuclear cells when activated by LPS or Staph lysate became cytotoxic in IN VITRO and IN VIVO assays. Lopez et al (6) have recently described the emergence of ‘Killer B lymphocytes’ in tumor bearing mice. These cells were shown to be ADCC effector cells.
GVH - Graft vs host VHR - Graft vs host reaction ADCC - Antibody dependent cellular cytotoxicity LPS - Lipopolysaccharide CMV - Cytomegalo virus EBV - Epstein Barr Virus SAC - Staphylococcus aureus strain Cowan I TD - Thymus dependent TI - Thymus independent CsA - Cyclosporine-A
Introduction B lymphocytes have long been known to be involved in the production of antibodies. Recent evidence from a few laboratories including ours indicates that they may participate in the effector
Date received 9 March 1989 Date accepted 18 August 1989
63
64 Thesis These observations prompted us to speculate that under suitable conditions, B lymphocytes of cancer and transplantation patients may get activated by a virus, bacterial antigen, alloantigen or T cell products. These activated B lymphocytes may cause GVH in immunosuppressed patients or cause tissue injury and allograft/tumor rejection. The mechanism of destruction of tissues or allografts may depend upon various factors. The activated B lymphocytes can cause the destruction directly, by ADCC mechanism, or they can produce lymphotoxins that can cause rejection or tissue damage. The activated B lymphocytes can produce soluble products which can influence the T lymphocytes, or affect other immunocompetent cells. While all these speculations remain to be resolved by experiments, the fact remains that B lymphocytes can be activated and they become cytotoxic. The following facts were also taken into consideration when the author proposed the hypothesis:
1) Infection
induces B cell proliferation without exogenous growth factors. B cells can be activated by viruses (7-9) 2) Infections following renal allograft transplantation are often caused by viruses like CMV. 3) Transplanted patients are under immunosuppressive regimen. Their situation resembles the immunosuppressed rats described in this paper. 4) Bacterial infection is usually accompanied by a significant increase in B cells as measured by flow cytometer using CD 20 marker (10). 5) B lymphocytes are known to produce lymphotoxins like TNF-fi (11). 6) Class II antigens activate the B lymphocytes (12) 7) SAC activates the human B cells. (13). 8) CsA affects the B cells differently depending upon the nature of the activating agents (TD or TI) (14).
Conclusion We postulate that B lymphoc tes may be involved in GVH and allograf J tumor rejection. While the author does not minimize the importance of T lymphocytes in GVHR or allograft rejection, the hypothesis offers another modality. other cells like eosinophils have been recently im-
MEDICAL HYPOTHESES
plicated in the graft rejection (15). Vascular endothelial system which cross reacts with monocyte antigens has been postulated for pathogenesis of rejection (16). One should not rule out the possibility of graft rejection by non-T cells including B lymphocytes either alone or in collaboration with one another directly or through their secretory products. Such an hypothesis may also be useful to diagnose the cancer patients and treat them with activated cells other than T cells. Work along these lines is in progress in our laboratory.
References 1. Welsh R M, Haspei M V, Parker D C, Holmes K V.
2. 3. 4. 5.
6.
7.
8.
9. 10.
11.
12.
Natural cvtotoxicitv against mouse hepatitis virus infected cells II-A cytotoxic &II with a B lymphocyte phenotype. JImmunoloev. 136: 1454. 1986. Bersani L, Colotta F, Peri G, Mantovani A. Cytotoxic effector function of B lymphoblasts. J. Immunology, 139: 645, 1987. Krishnan G, Capelli J P. B lymphocytes as effector cells. Human Immunology, 23: 115, 1988. Djerassi I, Ciesielka W, Krishnan G. In vivo and in vitro cytotoxic effects of live human B lymphoblast cells. Proc. AACR, 23: 402, 1988. Krishnan G, Dierassi I. Activation of cancer patients’ mononuclear cells by E.Coli lipopolysaccharide (LPS) and staphlysate (SPL) 7th International Congress of Immunology, Berlin 1989. Lopez M D, Blomberg B B, Padmanabhan R R, Bourguignon L Y W. Nuclear disintegration of target cells bv kill& lymphocytes from tumor-bearing mic;. FASEB Journal, 3: 37, 1988. Blazer B A, Sutton L M, Strom M. Self stimulating growth factor production by B cell lines derived from Burkitt’s lymphoma and other lines transformed in vitro by EB virus. Cancer Research, 43: 4562, 1983. Thorley-Lawson D A, Nadler L M, Bhan A K, Schooley R T. An early surface marker of human B cell activation is superimposed by EB virus. J. Immunology, 134: 3007, 1985. Gordon J, Walker L, Guv G, Brown G, Rowe M, Rickinson A. Control of B lymphocyte rephcation II. Immunoioav, 58(4): 59 1, 1986. Springgate--C F,> ‘Hussey J L, Hayes D H. Immune monitoring of transplant patients with monoclonal antibodies and flow cytometry. ASHIeQuarterly, 12(l): 21, 1988. Granger G A, Moore G E, White J G, et al. Production of lymphotoxin and migration inhibitory factor by established human lymphocytic cell lines. J. Immunology, 135: 1476, 1970. Moonev N, Grillot-Courvalin C, Hirvoz C, Charron D. Class II antigens can mediate lymphocyte activation. Human Immunoloev. 23(2): 126. 1988. Jurgensen C, Ambrus J,. Fauci A. Production of B cell growth factor by normal human B cells. J. Immunology, 136: 4542, 1986. “_
13.
B LYMPHOCYTES, ALLOGRAFP/TUMOR REJECPION AND GVH 14. Gery G B, Klaus. Cyclosporine sensitive and insensitive modes of B cell stimulation. Transplantation 46: lls-14s (supplement), 1988. 15. Kormendi F, Amand W J C Jr. The importance of
6.5
eosinophil cells in the kidney allograft rejection. Transplantation, 45: 537, 1988. 16. Reinitz E R, Tice D G. Calorimetric assay for monocyte expressed antigens. Transp. Proc. XIX, 1: 231, 1987.
Are B Lymphocytes Involved Rejection and GVH?
in Allograft/Tbmor
G. KRISHNAN Tissue-Typing
Laboratory,
Our Lady of Lourdes Medical Center, Camden,
NJ 08103, USA
Abstract - Several earlier observations by us and other investigators led us to propose a thesis that 6 lymphocytes, when activated by a virus, allo-antigen or bacterial protein would enter into effector arm of the immune response and cause allograft and tumor rejection or GVH-type of lesion in immunosuppressed animals. These effector cells may act directly in the process by contact with other cells or liberating cytokines. Such an hypothesis needs further support from experiments involving cancer and transplantation patients’ B cells.
Abbreviations
arm of the immune response.(l-5) Welsh et al (1) have demonstrated the existence of a cell with a B cell phenotype capable of lysing virus infected target cells in a 3h assay. Bersani et al (2) have reported the cytotoxic potential of a normal B-lymphoblastoid cell line by using actinomycin sensitive WEHIcells in 6h 51 Cr release assay. We (3, 4) showed that a normal B-lymphoblastoid cell line (RPMI-1788) caused GVH type of lesion in immunosuppressed rats, prolonged the survival of L-1210 tumor bearing DBA/2 mice by 3-5 days, released 51 Cr from 51 Cr K-562 cells in vitro and destroyed the human lung carcinoma cell line (A-549) in a monolayer flask. We (5) also showed that cancer mononuclear cells when activated by LPS or Staph lysate became cytotoxic in IN VITRO and IN VIVO assays. Lopez et al (6) have recently described the emergence of ‘Killer B lymphocytes’ in tumor bearing mice. These cells were shown to be ADCC effector cells.
GVH - Graft vs host VHR - Graft vs host reaction ADCC - Antibody dependent cellular cytotoxicity LPS - Lipopolysaccharide CMV - Cytomegalo virus EBV - Epstein Barr Virus SAC - Staphylococcus aureus strain Cowan I TD - Thymus dependent TI - Thymus independent CsA - Cyclosporine-A
Introduction B lymphocytes have long been known to be involved in the production of antibodies. Recent evidence from a few laboratories including ours indicates that they may participate in the effector
Date received 9 March 1989 Date accepted 18 August 1989
63
64 Thesis These observations prompted us to speculate that under suitable conditions, B lymphocytes of cancer and transplantation patients may get activated by a virus, bacterial antigen, alloantigen or T cell products. These activated B lymphocytes may cause GVH in immunosuppressed patients or cause tissue injury and allograft/tumor rejection. The mechanism of destruction of tissues or allografts may depend upon various factors. The activated B lymphocytes can cause the destruction directly, by ADCC mechanism, or they can produce lymphotoxins that can cause rejection or tissue damage. The activated B lymphocytes can produce soluble products which can influence the T lymphocytes, or affect other immunocompetent cells. While all these speculations remain to be resolved by experiments, the fact remains that B lymphocytes can be activated and they become cytotoxic. The following facts were also taken into consideration when the author proposed the hypothesis:
1) Infection
induces B cell proliferation without exogenous growth factors. B cells can be activated by viruses (7-9) 2) Infections following renal allograft transplantation are often caused by viruses like CMV. 3) Transplanted patients are under immunosuppressive regimen. Their situation resembles the immunosuppressed rats described in this paper. 4) Bacterial infection is usually accompanied by a significant increase in B cells as measured by flow cytometer using CD 20 marker (10). 5) B lymphocytes are known to produce lymphotoxins like TNF-fi (11). 6) Class II antigens activate the B lymphocytes (12) 7) SAC activates the human B cells. (13). 8) CsA affects the B cells differently depending upon the nature of the activating agents (TD or TI) (14).
Conclusion We postulate that B lymphoc tes may be involved in GVH and allograf J tumor rejection. While the author does not minimize the importance of T lymphocytes in GVHR or allograft rejection, the hypothesis offers another modality. other cells like eosinophils have been recently im-
MEDICAL HYPOTHESES
plicated in the graft rejection (15). Vascular endothelial system which cross reacts with monocyte antigens has been postulated for pathogenesis of rejection (16). One should not rule out the possibility of graft rejection by non-T cells including B lymphocytes either alone or in collaboration with one another directly or through their secretory products. Such an hypothesis may also be useful to diagnose the cancer patients and treat them with activated cells other than T cells. Work along these lines is in progress in our laboratory.
References 1. Welsh R M, Haspei M V, Parker D C, Holmes K V.
2. 3. 4. 5.
6.
7.
8.
9. 10.
11.
12.
Natural cvtotoxicitv against mouse hepatitis virus infected cells II-A cytotoxic &II with a B lymphocyte phenotype. JImmunoloev. 136: 1454. 1986. Bersani L, Colotta F, Peri G, Mantovani A. Cytotoxic effector function of B lymphoblasts. J. Immunology, 139: 645, 1987. Krishnan G, Capelli J P. B lymphocytes as effector cells. Human Immunology, 23: 115, 1988. Djerassi I, Ciesielka W, Krishnan G. In vivo and in vitro cytotoxic effects of live human B lymphoblast cells. Proc. AACR, 23: 402, 1988. Krishnan G, Dierassi I. Activation of cancer patients’ mononuclear cells by E.Coli lipopolysaccharide (LPS) and staphlysate (SPL) 7th International Congress of Immunology, Berlin 1989. Lopez M D, Blomberg B B, Padmanabhan R R, Bourguignon L Y W. Nuclear disintegration of target cells bv kill& lymphocytes from tumor-bearing mic;. FASEB Journal, 3: 37, 1988. Blazer B A, Sutton L M, Strom M. Self stimulating growth factor production by B cell lines derived from Burkitt’s lymphoma and other lines transformed in vitro by EB virus. Cancer Research, 43: 4562, 1983. Thorley-Lawson D A, Nadler L M, Bhan A K, Schooley R T. An early surface marker of human B cell activation is superimposed by EB virus. J. Immunology, 134: 3007, 1985. Gordon J, Walker L, Guv G, Brown G, Rowe M, Rickinson A. Control of B lymphocyte rephcation II. Immunoioav, 58(4): 59 1, 1986. Springgate--C F,> ‘Hussey J L, Hayes D H. Immune monitoring of transplant patients with monoclonal antibodies and flow cytometry. ASHIeQuarterly, 12(l): 21, 1988. Granger G A, Moore G E, White J G, et al. Production of lymphotoxin and migration inhibitory factor by established human lymphocytic cell lines. J. Immunology, 135: 1476, 1970. Moonev N, Grillot-Courvalin C, Hirvoz C, Charron D. Class II antigens can mediate lymphocyte activation. Human Immunoloev. 23(2): 126. 1988. Jurgensen C, Ambrus J,. Fauci A. Production of B cell growth factor by normal human B cells. J. Immunology, 136: 4542, 1986. “_
13.
B LYMPHOCYTES, ALLOGRAFP/TUMOR REJECPION AND GVH 14. Gery G B, Klaus. Cyclosporine sensitive and insensitive modes of B cell stimulation. Transplantation 46: lls-14s (supplement), 1988. 15. Kormendi F, Amand W J C Jr. The importance of
6.5
eosinophil cells in the kidney allograft rejection. Transplantation, 45: 537, 1988. 16. Reinitz E R, Tice D G. Calorimetric assay for monocyte expressed antigens. Transp. Proc. XIX, 1: 231, 1987.