Peyer's patches, thymus, and lymph nodes contain the majority of lymphocytes. We have studied proliferation rates, apoptosis rates, and numbers of B- and T-lymphocytes in Peyer's patches in ileum, thymus, and mesenterial and prescapular lymph nodes (LM and LP) in unfed preterm calves (GrP; born 13 d before expected normal term after dams were injected with prostaglandin F2alpha and glucocorticoids) and normal-term calves (GrF) immediately after birth and on d 5 of life after feeding colostrum for 4 d (GrC). Immunohistochemical methods in conjunction with incorporation of 5-bromo-2'-deoxyuridine or terminal deoxynucleotidyl transferase-mediated X-dUTP nick end labeling were used to evaluate cell proliferation rates and apoptosis rates, respectively. The number of T- and B-lymphocytes was determined with monoclonal antibodies directed against CD3 and CD79, respectively. In GrF compared with GrP, there were higher numbers of proliferating and apoptotic cells in LM and LP, of B-lymphocytes in paracortex and follicles of LM and LP, and of proliferating cells in cortex and medulla of thymus. In thymus cortex and medulla, numbers of proliferating cells were higher in GrC than in GrF. Apoptotic rates were generally smaller at all sites of Peyer's patches in GrC than in GrF, and proliferation rates increased from GrP to GrF in intrafollicular areas and from GrF to GrC in all tissues. Numbers of T-lymphocytes in Peyer's patches were higher in GrF than in GrP, but lower in GrC than in GrF, except in the domes. Numbers of B-lymphocytes did not change in Peyer's patches despite high proliferation and low apoptotic rates, suggesting that they leave Peyer's patches during the first days of life. In conclusion, proliferation and apoptosis rates and numbers of B- and T- lymphocytes in Peyer's patches in ileum, thymus, and LM and LP exhibited different developmental changes and were affected by feeding.

An increased susceptibility to disease in neonatal calves may be attributable to high glucocorticoid levels that influence immune reactions. We tested whether dexamethasone (DEXA) administration influences the proliferation, apoptosis, and number of B- and T-lymphocytes in Peyer's patches (PP) and thymus in calves fed colostrum (C) or a milk-derived formula. All calves were subcutaneously administered bovine colostrum-derived immunoglobulin G and fed chicken-egg derived immunoglobulins that protected against rotavirus and pathogenic Escherichia coli. The DEXA (30 microg/kg of BW daily) was injected for 4 d into groups fed colostrum on the first 3 d (CD+) and those fed the formula that contained nutrients in amounts as in colostrum but no immunoglubulin G (FD+). Groups CD- and FD were fed the same as the other two groups, but did not receive DEXA. Immunohistochemical methods were used to evaluate cell proliferation rates (by labeling of 5-bromo-2'-deoxyuridine), apoptosis rates (by terminal deoxynucleotidyl transferase-mediated X-dUTP nick end labeling). Numbers of T- and B-lymphocytes were determined with antibodies specific for CD3 and CD79 surface proteins. There were significant effects (P < 0.05) of DEXA treatment (decrease of cell proliferation rates in follicles of PP and thymus, increase of apoptotic rate in follicles of PP and thymus, decrease of B-lymphocyte numbers in follicles of PP, increase of B-lymphocyte numbers in domes of PP, increase of T-lymphocyte numbers in follicles of PP, and a decrease of intraepithelial T-lymphocyte numbers). There were significant effects (P < 0.05) of C feeding (decrease of cell proliferation rates in follicles of PP and of B-lymphocyte numbers in interfollicular areas, domes, and follicular-associated epithelium of PP, and an increase of cell proliferation rate in the thymus). A DEXA x feeding interaction (P < 0.001) was found for cell proliferation rate in the thymus. In conclusion, DEXA treatment decreased cell proliferation rates in follicles of PP and thymus and enhanced apoptotic rates in follicles of PP. Colostrum feeding decreased cell proliferation rates, likely of B-lymphocytes, in follicles of PP and numbers of B-lymphocytes in domes, follicular-associated epithelium, and interfollicular areas of PP and enhanced cell proliferation rates and selectively modified DEXA effects in the thymus.

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CD22 is a B cell-specific glycoprotein expressed on the cell surface of all mature B cells. A candidate therapeutic anti-CD22 antibody, 10F4v3, was conjugated to the anti-mitotic agent maytansine (10F4v3-DM1). DM1 disrupts cellular mitosis through inhibition of tubulin polymerization when internalized into cells. The anti-CD22 DM1 conjugate was shown to have significant potency in preclinical efficacy models of NHL. In order to further characterize this antibody-drug conjugate in preclinical studies, we first evaluated the binding characteristics of the 10F4v3 to peripheral blood B cells from various geographical sources of cynomolgus monkeys. 10F4v3 bound to peripheral blood B cells from all cynomolgus monkeys of Indonesian and Mauritian origins, but displayed only limited binding to cynomolgus monkeys of Chinese and Cambodian origins. Therefore, further pre-clinical evaluation of 10F4v3-DM1 was conducted in Indonesian cynomolgus monkeys to examine the safety, pharmacokinetic, and pharmacodynamic effects in monkeys dosed at 10, 20, and 30 mg/kg (2000, 4000, and 6000 mg/m2 DM1). Pharmacodynamic assessments of peripheral blood and lymphoid tissues included examination of B cells, B cell subsets, CD4+ T cells, CD8+ T cells, and CD3−CD20− (NK) cells. B cell subsets included CD20+, CD20+CD21+, CD20+CD21−, CD20+CD21+CD27+, CD20+CD21+CD27−, and CD20+CD21high lymphocytes which are phenotypically similar to human B cells, mature B cells, germinal center B cells, memory B cells, naïve B cells, and marginal zone B cells, respectively. B cells and B cell subsets were substantially depleted in peripheral blood at all doses, with no apparent dose-dependent effects. In lymphoid tissue, B cells were also depleted, with substantial depletion of CD20+CD21− and CD20+CD21high B cell subsets in spleen and bone marrow. Based on the nonclinical data, 10F4v3-DM1 exhibits an encouraging pharmacodynamic profile that supports clinical development for the potential treatment of non-Hodgkin’s lymphoma.

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