Background: Alemtuzumab (Campath-1H) is a humanized mAb directed against CD52 that depletes circulating but not bone marrow lymphocytes. A transient increase in proportion of circulating Treg is observed following its administration in humans. Very little is known about its influence on lymph nodes (LN), which play a central role in antigen presentation and serve as the main reservoir of circulating lymphocytes and Treg.
Methods: We investigated the influence of alemtuzumab on lymphocyte subsets and their subsequent repopulation in LN of Indonesian cynomolgus monkeys. Mesenteric and inguinal LN were harvested from (i) healthy controls (Gp 1, n=10), (ii) monkeys given various doses of alemtuzumab, but no transplant (Gp 2, n=6), and (iii) monkeys given 40 mg/kg alemtuzumab and an ABO-compatible heart transplant (Gp 3, n=5). LN were harvested at various time-points up to 1 yr after alemtuzumab. Absolute numbers of lymphocyte subsets, effector and memory T cells, and Treg were determined by flow cytometry.
Results: Normal LN contained 770 ± 290 x103 cells/mg tissue. Significant depletion of 75% and 87% to 191 ± 32 and 100 ± 81 x103 cells/mg was observed in Gps 3 and 2 at 2 d and 2 wks, respectively, which recovered to 538 ± 138 x103 cells/mg 12 mths post-alemtuzumab (Gp 2). CD3+T and CD20+B cells were equally depleted at d 2, but while CD3+T cells remained significantly reduced at 12 mths (42% total lymphocytes vs 71% in controls) CD20+B cells doubled (51% vs 25% in controls). Within CD3+T cells, the incidence of CD4+ T effector memory cells increased to 68.6% in Gp 3, and 70.0% in Gp 2, at 3 and 12 mths post-alemtuzumab, respectively, compared to 45.4% in controls, while decreased proportions of CD4+ naÏve T cells were observed. CD8+ T memory cells showed a similar trend. CD4+FoxP3+ Treg were reduced from 11.8% to 4.9% of CD4+ T cells by 3 mths.
Conclusions: Alemtuzumab profoundly depletes lymphocytes in monkey LN. CD3+ T cells are the the major population affected. Within recovering CD3+T cells there is an increased proportion of effector memory T cells. No difference between alemtuzumab only (Gp 2), and alemtuzumab plus transplant (Gp 3) was observed. Unlike observations on circulating lymphocytes, the incidence of Treg in the LN was reduced by alemtuzumab.
To cite this abstract in AMA style:Dons E, Windt Dvander, Tu L, Ezzelarab M, IJzermans J, Lakkis F, Cooper D, Thomson A. Differential Depletion and Recovery of Lymphocyte Subsets in Lymph Nodes of Alemtuzumab-Treated Cynomolgus Monkeys [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/differential-depletion-and-recovery-of-lymphocyte-subsets-in-lymph-nodes-of-alemtuzumab-treated-cynomolgus-monkeys/. Accessed December 7, 2019.
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