Abstract
In these studies, we examined the effect of a maximum-tolerated, split-dose chemotherapy protocol of cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea carmustine on neutrophil and lymphocyte subpopulations in the peripheral blood (PBL), thymus, bone marrow and spleen. It was found that this protocol of polychemotherapy, modeled after the induction protocol used with autologous bone marrow transplantation for breast cancer, suppressed both B and T cell populations and T cell function at times when the absolute neutrophil count had returned to normal or supernormal numbers. In the peripheral blood, 7 days following initiation of chemotherapy, there was a twofold increase in the percentage of granulocytes as compared to the level in control animals on the basis of a differential count. The polymorphonuclear neutrophil (PMN) frequency in the bone marrow was increased on day 14 and statistically identical to that in control mice on all other days analyzed. In contrast to the bone marrow cells and PBL on day 7, the frequency of PMN in the spleen and thymus was depressed. B cells (B220+) were depressed in the PBL, spleen and bone marrow and took 18–32 days to return to their normal frequency, while the frequency of B cells in the thymus was increased owing to a loss of immature T cells. The percentage of CD3+ cells in the thymus, spleen and bone marrow was significantly increased and required 10–18 days to return to normal levels, while the absolute number of CD3+ cells in the blood varied around the normal value. The ratio of CD4+ to CD8+ cells in all the organs studied varied only slightly owing to a similar reconstitution of CD4+ and CD8+ cells. In contrast to the phenotypic recovery of the CD3+, CD4+ and CD8+ cells, the ability of the splenic lymphocytes to respond to concanavalin-A was depressed and remained depressed, despite the phenotypic reconstitution of the T cell subsets, on the basis of both percentage and absolute cell number. These results show a selective T and B cell depression following multi-drug, split-dose chemotherapy in tissue and blood leukocyte populations and a chronic depression in T cell function.
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Carella AM, Frassoni F, Lint MT van, Gualandi E, Occhini D, Carlier P, Pollicardo N, Pungolino E, Fagioli F, Santini G, Congiu A, Nati S, Raffo MR, Podesta M, Corvo R, Vitale V, Gallamini A, Pogliani EM, Lanzi E, Bacigalupo A, Marmont A (1992) Autologous and allogenic bone marrow transplantation in acute myeloid leukemia in first complete remission: an update of the Genoa experience with 159 patients. Am Hematol 64: 128
Barrett AJ, Horowitz MM, Gale RP, Biggs JM, Carmitta BM, Dicke KA, Gluckman E, Good RA, Herzig RH, Lee MB, Marmont AM, Masaoka T, Ramsay NKC, Rimm AA, Speck B, Zwaan FE, Bortin MM (1989) Marrow transplantation for acute lymphoblastic leuemia: factors affecting relapse and survival. Blood 74: 862
Apperley JF, Jones L, Hale G, Waldmann H, Hows J, Pombos Y, Tsatalas C, Marcus RE, Goolden AWG, Gordon-Smith EC, Catovsky D, Galton DAG, Goldman JM (1987) Bone marrow transplantation for patients with chronic myeloid leukemia: T-cell depletion reduces the incidence of graft verses host disease but may increase the risk of leukemic relapse. Bone Marrow Transplant 1: 53
Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E, Hoffman RG, Jacobsen SJ, Marmont AM, McGlave PB, Messner HA, Rimm AA, Rozman C, Speck B, Tura S, Weiner RS, Borton MM (1988) Bone marrow transplantation for chronic myclogenous leukemia in chronic phase: increased risk of relapse associated with T-cell depletion. Ann Intern Medicine 108:806
Maranichi D, Gluckman E, Blaise D, Guyotote D, Dio B, Pico JL, Lebland V, Michallet M, Dreyfus F, Ifrah N, et al (1987) Impact of T-cell depletion on outcome of allogeneic bone marrow transplantation for standard risk leukemias. Lancet II: 175
Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED (1979) Anti-leukemia effects of graft-versus-host disease in human recipients of allogeneic marrow grafts. N Engl J Med 300: 1068
Bortin MM, Truitt RL, Rimm AA, Bach FM (1979) Graft-versusleukemia reactivity induced by alloimmunisation without augmentation of graft-versus-host reactivity. Nature 281: 490
Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L, Buckner CD, Anasetti C, Applebaum FR, Badger C, Beatty P, Bensinger W, Berenson R, Bigelow C, Cheever MA, Clift R, Deeg HJ, Doney K, Greenberg P, Hansen JA, Hill R, Loughran T, Martin P, Neiman P, Petersen FB, Sanders J, Sincer J, Stewart P, Thomas ED (1989) Influence of acute and chronic graft versus host disease on relapse and survival after bone marrow transplantation for HLA-identical siblings as treatment of acute and chronic leukemia. Blood 73: 1720
Clift RA, Buckner CD, Applebaum RF, Bearman SE, Petersen FB, Fisher LD, Anasetti C, Beatty P, Bensinger WI, Doney K, Hill RS, McDonald GB, Martin P, Sanders J, Singer J, Stewart P, Sullivan KM, Witherspoon R, Storb R, Hansen JA, Thomas ED (1990) Allogeneic marrow transplantation in patients with myeloid leukemia in first remission: a randomized trial of two irradiation regimes. Blood 76: 1867
Weiden PL, Sulbran KM, Flournoy N, Storb R, Thomas ED (1981) Antileukemic effect of chronic graft versus host disease: contribution to improve survival after allogeneic marrow transplantation. N Engl J Med 304: 1529
Butturini A, Bortin MM, Gale RP (1987) Influence of acute and chronic graft versus host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Bone Marrow Transplant 2: 233
Mackinnon S, Hows JM, Goldman JM (1990) Introduction of a syngeneic graft versus leukemia affect following bone marrow transplantation for chronic mycloid leukemia. Leukemia 4: 287
MacKinnon S, Hows JM, Goldman JM (1990) Induction of in vitro graft versus leukemia activity following bone marrow transplantation for chromic myeloid leukemia. Blood 76: 2037
Ringden O (1992) Allogeneic bone marrow transplantation. The Huddings experience. Transplant Proc 24: 371
Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringdén O, Rozman C, Speck B, Truitt RL, Zwaan FE, Bortin MM (1990) Graft-versus-leukemia reactions after bone marrow transplatation. Blood 75: 555
Sullivan KM, Witherspoon RP, Storb R, Weiden P, Flournoy N, Dahlberg S, Deeg HJ, Sanders JE, Dooney RC, Applebaum FR, et al (1988) Prednisone and azathioprine compared to prednisone and placebo for treatment of chronic graft verses host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation. Blood 72: 546
Harada M, Ueda M, Nakao S, Kondao S, Odaka K, Shibara S, Matoue K, Mori T, Hattori K, Tokai J (1985) Immunological reconstitution after allogeneic and autologous bone marrow transplantation. Exp Clin Med 10: 245
Witherspoon RP, Kopecky K, Storb RF, Fluornoy N, Sullivan KM, Sosa R, Deeg HJ, Ochs HD, Cheever MA, Thomas ED (1982) Immunological recovery in 48 patients following syngeneic marrow transplantations or hematological malignancy. Transplantation 33: 143
deGast GC, Verdonck LF, Middeldorp JM, The TA, Hekker A, Linden JA, Kreeft KAJG, Bast BJ (1985) Recovery of T-cell subset after autologous BMT is mainly due to proliferation of mature T-cells in the graft. Blood 66: 428
Miller RA, Daley J, Ghalie R, Kaizet H (1991) Clonal analysis of T-cell deficiencies in autotransplant recipient. Blood 77: 1845
Lum LG (1990) Immune recovery after BMT. Hematol Oncol Clin Am 4: 659
Atkinson K (1990) Reconstitution of the hemopoietic and immune systems after human marrow transplantation. Bone Marrow Transplant 5: 209
Lum LG (1987) The kinetics of immune reconstitution after human marrow transplantations. Blood 69: 369
Ault KA, Antin JH, Ginsburg D, Orkin SH, Rappeport JM, Keohan ML, Martin P, Smith BR (1985) Phenotype of recovering lymphoid cell populations after marrow transplantation. J Exp Med 161: 1483
Divine M, Lecouedic JP, Gourdin MF, Oudhriri N, Zohair M, Henni T, Bequjan F, Vernant JP, Reyes F, Farcet JP (1988) Functional analysis of CD-8 lymphocytes in long term surviving patients after BMT. Immunology 8: 140
Velardi A, Ternzi A, Cucciaioni S, Millo R, Grossi CE, Grignani F, Martelli MF (1988) Imbalances within the peripheral blood T helper (CD4−) and T suppressor (CD8+) cell populations in the reconstitution phase after human BMT. Blood 71: 196
Bensussan A, David V, Vilmer E, Leca G, Boumsell L (1990) Immunodeficiency after bone marrow transplantation can be associated with autoreactive T-cell receptor gamma delta-bearing lymphocytes. Immunol Rev 16: 5
Bengtsson M, Motterman TH, Smedmyr B, Festin R, Oberg G, Simonsson B (1989) Regeneration of function and activated NK and T-subset cells in the marrow and bone after autologous bone marrow transplantation: a prospective phenotypic study with 2/3 color FACS analysis. Leukemia 3: 68
Gebel HM, Kaizer H, Landay AL (1987) Characterization of circulating suppressor T lymphocytes in BMT recipients. Transplantation 43: 258
Odum N, Hofmann B, Jakobsen N, Langhoff E, Moller J, Platz P, Ryder LP, Svejgaard A (1987) The immunodeficiency of BMT patients. II. CD-8 related suppression by patient lymphocytes of the response of donor lymphocytes to mitogen, antigens, and allogeneic cells. Scand J Immunol 26: 247
Hercend T, Takvorian T, Nowill A, Tantravahi R, Moingeon P, Anderson K, Murray C, Bohvon C, Ythier A, Ritz J (1986) Characterization of NK cells with anti-leukemia activity following allogeneic bone marrow transplantation. Blood 67: 728
Niederwieser D, Gastl G, Rumpold H, Marth C, Kraft D, Huber C (1987) Rapid reappearance of large granular lymphocytes (LGL) with concomitant reconstitution of natural killer (NK) activity after human bone marrow transplantation. Br J Haematol 65: 301
Reittie JE, Gottlieb D, Heslop HE, Leger O, Drexler HG, Hazelhurst G, Hoffbrand AV, Prentice HG, Brenner MK (1989) Endogenously generated activated killer cells circulate after autologous and allogeneic marrow transplantation but not after chemotherapy. Blood 73: 1351
Peters WP (1990) Dose intensifiation using combination alkylating agents and autologous bone marrow support in the treatment of primary and metastic breast cancer: a review of the Duke Bone Marrow Transplantation Program experience. Prog Clin Biol Res 354B: 185
Talmadge JE, Fidler IJ, Oldham RK (1985) Screening for biological response modifiers: methods and rationale. Nijhoff, Dordrecht, p 1
Skorski T, Kawalee M, Ratajczak M, Szczylik C, Kawiak J (1990) Return of immunohematopoietic impairment a long time after murine syngeneic bone marrow transplantation. Bone Marrow Transplant 6: 315
Reinherz EL, Parkman R, Rappeport J, Roses FS, Schlossman SF (1979) Aberrations of suppressor T-cells in human graft-versushost disease. N Engl J Med 300: 1061
Bacigalupo A, Mingari MC, Moretta L, Posesta M, Lint MT van Piaggi Raffo MR, Marmont A (1981) Imbalance of T-cell subpopulations and defective pokeweed mitogen-induced B-cell differentiation after bone-marrow transplantation in man. Clin Immunol Immunopathol 2: 137
Friedrich W, OReilly RJ, Koziner B, Gebhard DE, Good RA, Evans RL (1982) T-lymphocyte reconstitution in recipients of bone-marrow transplants with and without GvHD. Imbalances of T-cell subpopulations having unique regulatory and cognitive functions. Blood 59: 696
Singer CRJ, Tannsey PJ, Burnett AK (1983) T-lymphocyte reconstitution following autologous bone marrow transplantation. Clin Exp Immunol 51: 455
LeBlanc G, Douay L, Laporte JP, Dominh A, Deloux J, Najman A, Duhamel G, Gorin NC (1986) Evaluation of lymphocyte subsets after autologous bone marrow transplantation with marrow treated by ASTA Z 7557 in acute leukemia: incidence of the in vitro treatment. Exp Hematol 14: 366
Ritz J, Sallan SE, Bast RC, Lipton JM, Clavell LA, Feeney M, Hercend T, Nathan DG, Schlossman SF (1982) Autologous bone marrow transplantation in CALLA-positive acute lymphoblastic leukemia after in vitro treatment with J-5 monoclonal antibody and complement. Lancet II: 60
Bengtsson M, Totterman TH, Smedmyr B, Festin R, Oberg G, Simonsson B (1989) Regeneration of functional and activated NK and T sub-subset cells in the marrow and blood after autologous bone marrow transplantation: a prospective phenotypic study with 2/3-color FACS analysis. Leukemia 3: 66
Gratama JW, Lipovich-Oosterveer MA, Willemze R, Slats J, DAmaro J, Verdonck LF, DeGast CC, Jansen J (1986) Reduction and repopulation of T-lymphocytes after cyto-reductive therapy with or without autologous bone marrow rescue. Exp Hematol 14: 172
Atkinson K, Hansen JA, Storb R, Goehle S, Goldstein G, Thomas ED (1982) T-cell subpopulations identified by monoclonal antibodies after human marrow transplantation. I. Helper-inducer and cytotoxic-supressor subsets. Blood 59: 714
Bruin HG de, Astaldi A, Leupers T, Griend RJ van de, Dooren LJ, Schellekens P, Tnke HJ, Roos M, Vossen JM (1981) I Lymphocyte characteristics in bone marrow-transplanted patients. II. Analysis with monoclonal antibodies. J Immunol 127: 244
Kast WM, DeWaal LP, Melief CJM (1984) Thymus dictates major histocompatibility complex (MHC) specificity and immune response gene phenotype of class II MHC-restricted T cells but not a class I MHC-restricted T cells. J Exp Med 160: 1752
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Talmadge, J.E., Jackson, J.D., Borgeson, C.D. et al. Differential recovery of polymorphonuclear neutrophils, B and T cell subpopulations in the thymus, bone marrow, spleen and blood of mice following split-dose polychemotherapy. Cancer Immunol Immunother 39, 59–67 (1994). https://doi.org/10.1007/BF01517182
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DOI: https://doi.org/10.1007/BF01517182