小鼠眼内移植性黑色素瘤及其相关免疫偏离的研究
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摘要
葡萄膜恶性黑色素瘤是成年人中转移和死亡率较高的一种眼内恶性肿瘤。
其病因及其发病机制目前尚不完全清楚，治疗措施有限，难以控制肿瘤的转
移。这可能与机体抗肿瘤免疫防御功能等某些因素有关。了解免疫系统能否接
受和影响葡萄膜黑色素瘤的行为，其最大的障碍是没有合适的措施评估脉络膜
黑色素瘤患者对黑色素瘤相关抗原的全身性免疫反应，而只能通过建立动物模
型来探索免疫系统的作用，对其相关的免疫学研究不多且尚无显著进展。
眼内肿瘤可得以独特的免疫赦免。将同种异体的黑色素瘤细胞接种于小鼠
皮下可引发抗原特异性迟发型超敏反应并被迅速排斥。而将其接种于眼前房后
肿瘤进行性生长，虽然也存在抗体反应和细胞毒T细胞反应，但产生了抗原特
异性迟发型超敏反应的持续性抑制。在20世纪80年代，Streilein等将这种复杂
的免疫调节过程称为前房相关免疫偏离（anterior chamber-associated immune
deviation，ACAID）。但目前尚不清楚玻璃体腔是否也存在这种现象。
眼的免疫赦免可以消除。ACAID可有利于眼内肿瘤的生存，不能诱导
ACAID的眼内肿瘤将不可避免地被排斥。适时切除脾脏可消除ACAID的诱导
而使眼内移植肿瘤的自发性消除。因此，消除眼的免疫赦免而诱发眼内肿瘤的
排斥反应，保存眼组织功能，将可能是发展合理治疗眼内肿瘤的重要策略之
本实验旨在了解异系小鼠前房和玻璃体腔移植性黑色素瘤及其相关免疫偏
离的关系，以及消除其相关免疫偏离和瘤苗接种等免疫治疗措施对眼内恶性黑
色素瘤生长的影响。
暨南人学博I：学位论义（刀01）小鼠眼内移植件黑色素痫及几相关免疫偏离的研究
第一部分小鼠眼内移植性黑色素瘤模型的建立
目的 建立小鼠前房和玻璃体腔同种异体移植性黑色素瘤模型，以作其与眼兔疫
赦免的相关研究。
－方法 将传代培养的恶性黑色素瘤B16F10细胞分别移植接种于3组昆明小鼠的
右前房、右玻璃体腔或右足背皮下。以裂隙灯和手术显微镜等观察肿瘤的生长
情况共32天，观察记录肿瘤的发生率、荷瘤眼溃破时间及瘤体生长曲线，并作
统计学分析。最后作病理观察。
结果1．昆明小鼠移植性黑色素瘤的发生率分别为前房组12／12眼，玻璃体腔组
11／11眼和足背皮下2／12只。前两组的肿瘤发生率明显较高（P＝0．000）。2．荷
瘤眼的溃破时间分别为前房组11～13天，玻璃体腔组13～32”天。玻璃体腔荷
瘤组的眼球生存期较长（Kaplan－Meter生存率曲线 P刃．000）。3．在观察后期
可见眼内黑色素瘤突破眼球后可向眶内生长，继而萎缩脱落。荷瘤鼠仍存活。
第32天的瘤体平均直径分别为前房组2．27士1．97mm，玻璃体腔组3．82土
1．85mm和皮下黑色素瘤组0．94土2．27nun。玻璃体腔组与皮下组之间的差异具
有非常显著性意义（＝0．003、4．病理观察中，眼内肿瘤未见坏死灶，而皮下肿
瘤可见中央部坏死。荷瘤鼠的肝、脾、肺和淋巴结未见转移灶。
结论＊同种异体黑色素瘤在昆明小鼠前房和玻璃体腔均被免疫赦免，而在皮下
则被兔疫排斥。2．it房和玻璃体腔对移植性黑色素瘤的免疫赦免可能有一定的
差别。3．昆明小鼠iiJ房和玻璃体腔移植性黑色素瘤可重复性好，能模拟人类葡
旦 萄膜恶性黑色素瘤的眼内生长过程，是研究眼内黑色素瘤与免疫赦免的理想模
型。
第二部分眼内黑色素瘤诱导兔疫偏离的表达及其测定
目的 观察小鼠前房和玻璃体腔的移植性黑色素瘤是否具有诱导免疫偏离的能
力。
2
暨南人学助I：学位论义（2皿】）小鼠眼内移植性黑色素痈及儿相关免疫偏离的研究
方法 饲养雄性昆明小鼠60只共随机分5组。在实验组的前房或玻璃体腔分别
接种黑色素瘤B16F10细胞；对照组则于相应部位注入相应量的HBSS；再设常
规免疫对照组。五天后在5组小鼠右足背皮下均注射黑色素瘤细胞作一免。十
天后在5组小鼠的右耳背皮下均注射黑色素瘤细胞作二免，而在左耳背皮下注
玉 射等量的HBSS作对照。应用超声角膜测厚仪测量双耳廓二免前后的厚度，计
算右耳的肿胀量，并作统计学分析。选择切取实验组和对照组部分耳廓作病理
切片检查。
结果1．昆明小鼠前房和玻璃体腔移植性黑色素瘤均可进行性生长。2．各组
右耳肿胀量分别为：前房实验组 34土35 pm，玻璃体腔实验组 36士96 Pm，前
房对照组194土99 Pm，玻璃体腔对照组186土55 Pm，常规兔疫组165土118 Pm。
实验组与对照组之间右耳肿胀量的的差异具有显著性甚至是非常显著性意义前
MS＠ HHW4 86uMde＠ j＆deXMi？～viDZ＝～w H
Uveal melanoma is a tumor with a high incidenee of metastasis and a
high mortality rate. To control the intraocular tuWr and make an
effective treatment of metastases, further research oll itS pathogenesis is
necessary. There is a special relation betWeen uveal melanoma and
immune system, but it is hard to observe the immune resPOnse on patients
in vivo for lacking of proper method. Establishing animal models with
intraocular melanoma is a valuable way.
There may be immune privilege in eye fOr intracular tUmors.
Allogenic tumors inoculated into anterior chamber of the eye in mice
were able to result in progressively growing intraocular tUmors and
imPaired delayed-type hyPersensitivity (DTH) reaCtivity, but produeed
normal humoral antibodies and cytotoxic T cells sPecific for melanoma
cells. By contrast, subcutaneous inoculation of melanoma cells induced
significant DTH resPonses tO the alloantigens expressed on the tumor
cells and stimulated brisk rejection of the subcutaneously injected tumor
cells. This pattern of immunological impairment has been termed anterior
chamber-associated immune deviation (ACAID) by Streilein in 1980s. It
is not clear whether this phenomenon exists in vitreous cavity (VC).
The immune privilege in eye for intraocular tumor is able to be
abrogated. Intraocular tumors growing is owing to ACAID, but it will be
rejected when the ACAlD disaPPear such as aPpropriately timed
splenectomy. Therefore, theraPeutic protocols using sPecific
immunization are able to be devised to induce hosts bearing intraocular
tumors to mount immune response very vigorously tO destroy the tumor
in the eye, and sufficiently precise to preserve the fUnctional and
anatomic integrity of the eye precisely.
Our research mainly observed whether allogeneic intraocular
melanoma could induce ACAlD and vitreous cavity-associated inunne
deviation (VCAlD) in Kunming ndce. If it could, what effect will be
found in hosts bearing intraocuar tumors when the associated immune
deviation was abrogated and tumor cell vaCCine was aPPlied.
Part I Establishing Intraocular Mclanoma modeIs in Mice
PURPOSE. To Establish an allogenic intraocular melanoma model in
Mice fOr stUding immune privilege of eyes.
METHODS. Allogeneic melanoma cells B16F10 (C57BU6) was
inoculated into anterior chamber (AC or vitreous cavity (VC) or
subcutaneous (SC) in Kunming mice with three groups. The tumor
growing status were observed by slip-lamP biomicroscopy and operating
microscopy for 32 days. The incidence of tumor and time of eyeball
diabrosis and size of the tumor were recorded fOr statistics analysis.
Pathological examination was given for tumors at last.
RESULTS. 1. The incidence of tumor in both AC grouP (12/12 eyes)
and VC grouP (12/12 eyes) was higher than that in SC group (2/12
foots)(T-test: P=0.000). 2. The time of eyeball diabrosis was 11~13
days in AC group and 13--32+ days in VC group, and there was
significant difference in this tWo groups (KaPlan(Meier survival analysis:
P=0.000). 3. The intraocular melanomas could grow progressively
outside eyeball for a period, then it reduced and fell off All the mice
were also alive. The size of the tumor on 32th days was 2.27I 1.97mm
in AC grouP, 3.82f 1.85mm in VC grouP and 0.94 f2.27nun in SC
groupo There was significant difference of that betwCen VC and SC
grouP (P=0.003). 4. Tumor tissue necrosis on the center of the
subcutaneous melanomas could be observed in pathOlogical examination,
but not in intraocular melanomas. Tumor metastasis could not be found
in the liver, spleen, and nodi lymPhatica.
CONCLUSION. 1. Allogeneic tumor cells was exPressed progressive
growth of intraocular tumors and transient growth of allogeneic tllmors
injected suboutaneously. 2. The ways in which allogeneic tUmor cells
induced immune privilege may be different betWeen AC and VC. 3.
Allogenic intraocular melanomas in mice are good models in studing
immune privilege of eyes for its growth is similar to tha
其病因及其发病机制目前尚不完全清楚，治疗措施有限，难以控制肿瘤的转
移。这可能与机体抗肿瘤免疫防御功能等某些因素有关。了解免疫系统能否接
受和影响葡萄膜黑色素瘤的行为，其最大的障碍是没有合适的措施评估脉络膜
黑色素瘤患者对黑色素瘤相关抗原的全身性免疫反应，而只能通过建立动物模
型来探索免疫系统的作用，对其相关的免疫学研究不多且尚无显著进展。
眼内肿瘤可得以独特的免疫赦免。将同种异体的黑色素瘤细胞接种于小鼠
皮下可引发抗原特异性迟发型超敏反应并被迅速排斥。而将其接种于眼前房后
肿瘤进行性生长，虽然也存在抗体反应和细胞毒T细胞反应，但产生了抗原特
异性迟发型超敏反应的持续性抑制。在20世纪80年代，Streilein等将这种复杂
的免疫调节过程称为前房相关免疫偏离（anterior chamber-associated immune
deviation，ACAID）。但目前尚不清楚玻璃体腔是否也存在这种现象。
眼的免疫赦免可以消除。ACAID可有利于眼内肿瘤的生存，不能诱导
ACAID的眼内肿瘤将不可避免地被排斥。适时切除脾脏可消除ACAID的诱导
而使眼内移植肿瘤的自发性消除。因此，消除眼的免疫赦免而诱发眼内肿瘤的
排斥反应，保存眼组织功能，将可能是发展合理治疗眼内肿瘤的重要策略之
本实验旨在了解异系小鼠前房和玻璃体腔移植性黑色素瘤及其相关免疫偏
离的关系，以及消除其相关免疫偏离和瘤苗接种等免疫治疗措施对眼内恶性黑
色素瘤生长的影响。
暨南人学博I：学位论义（刀01）小鼠眼内移植件黑色素痫及几相关免疫偏离的研究
第一部分小鼠眼内移植性黑色素瘤模型的建立
目的 建立小鼠前房和玻璃体腔同种异体移植性黑色素瘤模型，以作其与眼兔疫
赦免的相关研究。
－方法 将传代培养的恶性黑色素瘤B16F10细胞分别移植接种于3组昆明小鼠的
右前房、右玻璃体腔或右足背皮下。以裂隙灯和手术显微镜等观察肿瘤的生长
情况共32天，观察记录肿瘤的发生率、荷瘤眼溃破时间及瘤体生长曲线，并作
统计学分析。最后作病理观察。
结果1．昆明小鼠移植性黑色素瘤的发生率分别为前房组12／12眼，玻璃体腔组
11／11眼和足背皮下2／12只。前两组的肿瘤发生率明显较高（P＝0．000）。2．荷
瘤眼的溃破时间分别为前房组11～13天，玻璃体腔组13～32”天。玻璃体腔荷
瘤组的眼球生存期较长（Kaplan－Meter生存率曲线 P刃．000）。3．在观察后期
可见眼内黑色素瘤突破眼球后可向眶内生长，继而萎缩脱落。荷瘤鼠仍存活。
第32天的瘤体平均直径分别为前房组2．27士1．97mm，玻璃体腔组3．82土
1．85mm和皮下黑色素瘤组0．94土2．27nun。玻璃体腔组与皮下组之间的差异具
有非常显著性意义（＝0．003、4．病理观察中，眼内肿瘤未见坏死灶，而皮下肿
瘤可见中央部坏死。荷瘤鼠的肝、脾、肺和淋巴结未见转移灶。
结论＊同种异体黑色素瘤在昆明小鼠前房和玻璃体腔均被免疫赦免，而在皮下
则被兔疫排斥。2．it房和玻璃体腔对移植性黑色素瘤的免疫赦免可能有一定的
差别。3．昆明小鼠iiJ房和玻璃体腔移植性黑色素瘤可重复性好，能模拟人类葡
旦 萄膜恶性黑色素瘤的眼内生长过程，是研究眼内黑色素瘤与免疫赦免的理想模
型。
第二部分眼内黑色素瘤诱导兔疫偏离的表达及其测定
目的 观察小鼠前房和玻璃体腔的移植性黑色素瘤是否具有诱导免疫偏离的能
力。
2
暨南人学助I：学位论义（2皿】）小鼠眼内移植性黑色素痈及儿相关免疫偏离的研究
方法 饲养雄性昆明小鼠60只共随机分5组。在实验组的前房或玻璃体腔分别
接种黑色素瘤B16F10细胞；对照组则于相应部位注入相应量的HBSS；再设常
规免疫对照组。五天后在5组小鼠右足背皮下均注射黑色素瘤细胞作一免。十
天后在5组小鼠的右耳背皮下均注射黑色素瘤细胞作二免，而在左耳背皮下注
玉 射等量的HBSS作对照。应用超声角膜测厚仪测量双耳廓二免前后的厚度，计
算右耳的肿胀量，并作统计学分析。选择切取实验组和对照组部分耳廓作病理
切片检查。
结果1．昆明小鼠前房和玻璃体腔移植性黑色素瘤均可进行性生长。2．各组
右耳肿胀量分别为：前房实验组 34土35 pm，玻璃体腔实验组 36士96 Pm，前
房对照组194土99 Pm，玻璃体腔对照组186土55 Pm，常规兔疫组165土118 Pm。
实验组与对照组之间右耳肿胀量的的差异具有显著性甚至是非常显著性意义前
MS＠ HHW4 86uMde＠ j＆deXMi？～viDZ＝～w H
Uveal melanoma is a tumor with a high incidenee of metastasis and a
high mortality rate. To control the intraocular tuWr and make an
effective treatment of metastases, further research oll itS pathogenesis is
necessary. There is a special relation betWeen uveal melanoma and
immune system, but it is hard to observe the immune resPOnse on patients
in vivo for lacking of proper method. Establishing animal models with
intraocular melanoma is a valuable way.
There may be immune privilege in eye fOr intracular tUmors.
Allogenic tumors inoculated into anterior chamber of the eye in mice
were able to result in progressively growing intraocular tUmors and
imPaired delayed-type hyPersensitivity (DTH) reaCtivity, but produeed
normal humoral antibodies and cytotoxic T cells sPecific for melanoma
cells. By contrast, subcutaneous inoculation of melanoma cells induced
significant DTH resPonses tO the alloantigens expressed on the tumor
cells and stimulated brisk rejection of the subcutaneously injected tumor
cells. This pattern of immunological impairment has been termed anterior
chamber-associated immune deviation (ACAID) by Streilein in 1980s. It
is not clear whether this phenomenon exists in vitreous cavity (VC).
The immune privilege in eye for intraocular tumor is able to be
abrogated. Intraocular tumors growing is owing to ACAID, but it will be
rejected when the ACAlD disaPPear such as aPpropriately timed
splenectomy. Therefore, theraPeutic protocols using sPecific
immunization are able to be devised to induce hosts bearing intraocular
tumors to mount immune response very vigorously tO destroy the tumor
in the eye, and sufficiently precise to preserve the fUnctional and
anatomic integrity of the eye precisely.
Our research mainly observed whether allogeneic intraocular
melanoma could induce ACAlD and vitreous cavity-associated inunne
deviation (VCAlD) in Kunming ndce. If it could, what effect will be
found in hosts bearing intraocuar tumors when the associated immune
deviation was abrogated and tumor cell vaCCine was aPPlied.
Part I Establishing Intraocular Mclanoma modeIs in Mice
PURPOSE. To Establish an allogenic intraocular melanoma model in
Mice fOr stUding immune privilege of eyes.
METHODS. Allogeneic melanoma cells B16F10 (C57BU6) was
inoculated into anterior chamber (AC or vitreous cavity (VC) or
subcutaneous (SC) in Kunming mice with three groups. The tumor
growing status were observed by slip-lamP biomicroscopy and operating
microscopy for 32 days. The incidence of tumor and time of eyeball
diabrosis and size of the tumor were recorded fOr statistics analysis.
Pathological examination was given for tumors at last.
RESULTS. 1. The incidence of tumor in both AC grouP (12/12 eyes)
and VC grouP (12/12 eyes) was higher than that in SC group (2/12
foots)(T-test: P=0.000). 2. The time of eyeball diabrosis was 11~13
days in AC group and 13--32+ days in VC group, and there was
significant difference in this tWo groups (KaPlan(Meier survival analysis:
P=0.000). 3. The intraocular melanomas could grow progressively
outside eyeball for a period, then it reduced and fell off All the mice
were also alive. The size of the tumor on 32th days was 2.27I 1.97mm
in AC grouP, 3.82f 1.85mm in VC grouP and 0.94 f2.27nun in SC
groupo There was significant difference of that betwCen VC and SC
grouP (P=0.003). 4. Tumor tissue necrosis on the center of the
subcutaneous melanomas could be observed in pathOlogical examination,
but not in intraocular melanomas. Tumor metastasis could not be found
in the liver, spleen, and nodi lymPhatica.
CONCLUSION. 1. Allogeneic tumor cells was exPressed progressive
growth of intraocular tumors and transient growth of allogeneic tllmors
injected suboutaneously. 2. The ways in which allogeneic tUmor cells
induced immune privilege may be different betWeen AC and VC. 3.
Allogenic intraocular melanomas in mice are good models in studing
immune privilege of eyes for its growth is similar to tha
引文
1．马景学．后部葡萄膜恶性黑色素瘤-流行病学及临床病理学特征．中华眼底病杂志，1997，13：57．
2．庞友鉴，李佩莲．常见眼部肿瘤与眼眶病．北京医科大学中国协和医科大学联合出版社，北京．1995年6月，第一版：83．
3．郭秉宽．色素膜黑色素瘤的临床和病理(65例的总结分析)．中华眼科杂志，1978；14：16．
4．郭青，郭金凤．眼脉络膜恶性黑色素瘤治疗的进展．眼科研究，1998；16：78．
5.McLean IW, Zimmerman LE, Foster WD. Survival rates after enucleation of eyes with malignant melanoma. Am J Ophthalmol 1979;88:794.
6.Shields JA, Augsburger JJ, Donoso LA, et al. Hepatic metastasis and orbital recurrence of uveal melanoma after 42 years. Am J Ophthalmol, 1985; 100:666.
7.Ashon N. Primary tumors of the iris. Br J Ophthal, 1964;48:650.
8.Ksander BR, Rubsamen P, Olsen K, et al. Studies of tumor-infiltrating lymphocytes from a choroidal melanoma. Invest Ophthalmol Vis Sci, 1992; 32:3198.
9.Greene HSN, Lund PK. The heterologous transplantation of human cancers. Cancer Res, 1944; 4:352.
10.Char DH, Hollinshead A, Gogan DG, et al. Cutaneous delayed hypersensitivity reaction to soluble melanoma antigen in patients with ocular melonoma. N Eng J Med, 1974; 291:274.
11.Cochran AJ, Foulds WS, Damato BE, et al. Assessment of immunological techniques in diagnosis of ocular malignant melanoma. Br J Ophthalmol, 1985; 69:171.
12.Kan-Mitchell J, Liggett PE, Harel W, et al. Lymphocytes cytotoxic ti uveal and skin melanoma cells from peripheral blood of ocular melanoma patients. Cancer Immunol Immunother, 1991; 33:333.
13.Niederkorn JY, Streilein JW, Shadduck JA, et al. Deviant immune responses to allogeneic tumors injected intracamerally and subcutaneously in mice. Invest Ophthalmol Vis Sci, 1981; 20:355.
14．李志杰，李辰．眼免疫赦免的现代概念及临床意义．国外医学眼科学分册，
1996; 20: 129．
15． Benson JL, Niederkorn JY. In situ suppression of delayed-type hypersensitivity: another mechanism for sustaining the immune privilege of the anterior chamber. Immunology, 1991; 74:153．
16． Ma D, Alizadeh H, Comerford SA, et al. Rejection of intraocular tumors from transgenic mice by tumor-infiltrating lymphocytes. Curr Eye Res, 1994; 13:361．
17． Gosling WRO, Blom DJR, de Waard-Siebinga I, et al. Membrane bound regulators of completment activation in uveal melanoma. Invest Ophthalmol Vis Sci, 1996; 37:1884．
18． Lang JR, Davidorf FH, Baba N. The prognostic significance of lymphocytic infiltration in malignant melanoma of the chorooid. Cancer, 1977; 40:2388．
19． Dune FH, Campbell AM, Lee WR, et al. Analysis of lymphocytic infiltration in uveal melanoma. Invest Ophthalmol Vis Sci, 1990; 31:2106．
20． Meecham WJ, Char DH, Kaleta-Michaels S. Infiltrating lymphocytes and antigen expression in uveal melanoma. Ophthalmic Res, 1992; 24:2．
21． Ksander BR, Rubsamen PE, Olsen KR, et al. Studies of tumor-infiltrating lymphocytes from a human choroidal melanoma. Invest Ophthalmol Vis Sci, 1991; 32:3198．
22． Kremer I, Gilad E, Kahan E, et al. Necrosis and lymphocytic infiltration in choroidal melanomas. Acta Ophthalmol, 1991; 69:347．
23． Whelchel JC, Farah SE, McLean IW, et al. Immunochemistry of infiltrating lymphocytes in uveal melanoma. Invest Ophthalmol Vis Sci, 1993; 34:2603．
24． Nitta T, Oksenberg JR, Rao NA, et al. Predominant expression of T cell receptor V a 7 in tumor-infiltrating-lymphocytes of uveal melanoma. Science, 1990; 249:672．
25． Dune FH, George WD, Campbell AM, Damato BE. Analysis of clonality of tumour infiltrating lymphocytes in breast cancer and uveal melanoma. Immunol
Lett, 1992; 33:263．
26． Knisely TL, Niederkorn JY. Emergence of a dominant cytotoxic T Imphocyte (CTL) antitumor effector from tumor infiltrating cells in the anterior chamber of the eye. Cancer Immunol Immunother, 1990; 30:323．
27． Ma D, Alizadeh H, Comerfbrd SA, et al. Rejection of intraocular tumors from transgenic mice by tumor-infiltrating lymphocytes. Curr Eye Res, 1994; 13:361．
28． Apte R, Niederkorn JY. Isolation and characterization of a unique natural killer cell inhibitory factor present in the anterior chamber of the eye. J Immunol, 1996; 156:2667．
29． Rook AH, Kehrl JH, Wakefidd LM, et al. Effects of transforming growth factor-β on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol, 1986; 136:3916．
30． Ma D, Luyten GP, Luider TM, et al. Relationship between natural killer cell susceptibility and metastasis of human uveal melanoma cells in a murine model. Invest Ophthalmol Vis Sci, 1995; 36:435．
31． Tanihara H, Yoshida M, Matsumoto M, et al. Identification of transforming growth factor-β expressed in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci,1993; 34:413．
32． Connor TB Jr, Roberts AB, Sporn MB, et al. Correlation of fibrosis and transforming growth factor-β type 2 levels in the eye. J Clin Invest, 1989; 83:1661．
33． Huang XQ, Mitchell MS, Liggett PE, et al. Non-fastidious, melanoma-specific CD8+ cytotoxic T lymphocytes from choroidal melanoma patients. Cancer Immunol Immunother, 1994; 38:399．
34． Niederkorn JY, Streilein JW. Induction of anterior chamber-associated immune deviation (ACAID) by allogeneic intraocular tumors dose not require splenic metastases. J Immunol, 1982; 128:2470．
35.Niederkorn JY. Suppressed cellular immunity in mice harboring intraocular melanomas. Invest Ophthalmol Vis Sci, 1984; 25:447.
36.Streilein JW, Niederkorn JY. Induction of anterior chamber-associated immune deviation requires an intact functional spleen. J Exp Med, 1981; 153:1058.
37.Knisely TL, Luckenbach MW, Fischer BJ, et al. Destructive and nondestructive patterns of immune rejection of syngeneic intraocular tumors. J Immunol, 1987;138:4515.
38.Niederkorn JY, Streilein JW. Lymphoma allografts abrogate immune privilege within the anterior chamber of the eye. Invest Ophthalmol Vis Sci, 1986; 27:1235.
39.Niederkorn JY. Exogenous recombination interleukin-2 abrogates anterior chamber-associated immune deviation. Transplantation, 1987; 43:523.
40.Miki S, Ksander BR, Streilein JW. Complete elimination of progressively growing intraocular tumors by local injection of tumor-specific CD8~+ T lymphocytes. Invest Ophthalmol Vis Sci, 1993; 34:3622.
41.Soiffer RJ, Chapman PB, Murray C, et al. Administration of R24 monoclonal antibody and low-dose interleukin 2 for malignant melanoma. Clin Cancer Res, 1997; 3:17.
42.Ma D, Niederkorn JY. Role of epidermal growth factor receptor in the metastasis of intraocular melanomas. Invest Ophthalmol Vis Sci, 1998; 39:1067.
43.Luckenbach MW, Streilein JW, Niederkorn JY. Histopathologic analysis of intraocular allogeneic tumors in mice. Invest Ophthalmol Vis Sci, 1985; 26:1368.
44.Schurmans LR, den Boer AT, Diehl L, et al. Successful immunotherapy of an intraocular tumor in mice. Cancer Res, 1999;59:5250.
45．孟宁，李志杰．眼内肿瘤与眼免疫赦免．中华眼底病杂志，2000；16：67．
2．庞友鉴，李佩莲．常见眼部肿瘤与眼眶病．北京医科大学中国协和医科大学联合出版社，北京．1995年6月，第一版：83．
3．郭秉宽．色素膜黑色素瘤的临床和病理(65例的总结分析)．中华眼科杂志，1978；14：16．
4．郭青，郭金凤．眼脉络膜恶性黑色素瘤治疗的进展．眼科研究，1998；16：78．
5.McLean IW, Zimmerman LE, Foster WD. Survival rates after enucleation of eyes with malignant melanoma. Am J Ophthalmol 1979;88:794.
6.Shields JA, Augsburger JJ, Donoso LA, et al. Hepatic metastasis and orbital recurrence of uveal melanoma after 42 years. Am J Ophthalmol, 1985; 100:666.
7.Ashon N. Primary tumors of the iris. Br J Ophthal, 1964;48:650.
8.Ksander BR, Rubsamen P, Olsen K, et al. Studies of tumor-infiltrating lymphocytes from a choroidal melanoma. Invest Ophthalmol Vis Sci, 1992; 32:3198.
9.Greene HSN, Lund PK. The heterologous transplantation of human cancers. Cancer Res, 1944; 4:352.
10.Char DH, Hollinshead A, Gogan DG, et al. Cutaneous delayed hypersensitivity reaction to soluble melanoma antigen in patients with ocular melonoma. N Eng J Med, 1974; 291:274.
11.Cochran AJ, Foulds WS, Damato BE, et al. Assessment of immunological techniques in diagnosis of ocular malignant melanoma. Br J Ophthalmol, 1985; 69:171.
12.Kan-Mitchell J, Liggett PE, Harel W, et al. Lymphocytes cytotoxic ti uveal and skin melanoma cells from peripheral blood of ocular melanoma patients. Cancer Immunol Immunother, 1991; 33:333.
13.Niederkorn JY, Streilein JW, Shadduck JA, et al. Deviant immune responses to allogeneic tumors injected intracamerally and subcutaneously in mice. Invest Ophthalmol Vis Sci, 1981; 20:355.
14．李志杰，李辰．眼免疫赦免的现代概念及临床意义．国外医学眼科学分册，
1996; 20: 129．
15． Benson JL, Niederkorn JY. In situ suppression of delayed-type hypersensitivity: another mechanism for sustaining the immune privilege of the anterior chamber. Immunology, 1991; 74:153．
16． Ma D, Alizadeh H, Comerford SA, et al. Rejection of intraocular tumors from transgenic mice by tumor-infiltrating lymphocytes. Curr Eye Res, 1994; 13:361．
17． Gosling WRO, Blom DJR, de Waard-Siebinga I, et al. Membrane bound regulators of completment activation in uveal melanoma. Invest Ophthalmol Vis Sci, 1996; 37:1884．
18． Lang JR, Davidorf FH, Baba N. The prognostic significance of lymphocytic infiltration in malignant melanoma of the chorooid. Cancer, 1977; 40:2388．
19． Dune FH, Campbell AM, Lee WR, et al. Analysis of lymphocytic infiltration in uveal melanoma. Invest Ophthalmol Vis Sci, 1990; 31:2106．
20． Meecham WJ, Char DH, Kaleta-Michaels S. Infiltrating lymphocytes and antigen expression in uveal melanoma. Ophthalmic Res, 1992; 24:2．
21． Ksander BR, Rubsamen PE, Olsen KR, et al. Studies of tumor-infiltrating lymphocytes from a human choroidal melanoma. Invest Ophthalmol Vis Sci, 1991; 32:3198．
22． Kremer I, Gilad E, Kahan E, et al. Necrosis and lymphocytic infiltration in choroidal melanomas. Acta Ophthalmol, 1991; 69:347．
23． Whelchel JC, Farah SE, McLean IW, et al. Immunochemistry of infiltrating lymphocytes in uveal melanoma. Invest Ophthalmol Vis Sci, 1993; 34:2603．
24． Nitta T, Oksenberg JR, Rao NA, et al. Predominant expression of T cell receptor V a 7 in tumor-infiltrating-lymphocytes of uveal melanoma. Science, 1990; 249:672．
25． Dune FH, George WD, Campbell AM, Damato BE. Analysis of clonality of tumour infiltrating lymphocytes in breast cancer and uveal melanoma. Immunol
Lett, 1992; 33:263．
26． Knisely TL, Niederkorn JY. Emergence of a dominant cytotoxic T Imphocyte (CTL) antitumor effector from tumor infiltrating cells in the anterior chamber of the eye. Cancer Immunol Immunother, 1990; 30:323．
27． Ma D, Alizadeh H, Comerfbrd SA, et al. Rejection of intraocular tumors from transgenic mice by tumor-infiltrating lymphocytes. Curr Eye Res, 1994; 13:361．
28． Apte R, Niederkorn JY. Isolation and characterization of a unique natural killer cell inhibitory factor present in the anterior chamber of the eye. J Immunol, 1996; 156:2667．
29． Rook AH, Kehrl JH, Wakefidd LM, et al. Effects of transforming growth factor-β on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol, 1986; 136:3916．
30． Ma D, Luyten GP, Luider TM, et al. Relationship between natural killer cell susceptibility and metastasis of human uveal melanoma cells in a murine model. Invest Ophthalmol Vis Sci, 1995; 36:435．
31． Tanihara H, Yoshida M, Matsumoto M, et al. Identification of transforming growth factor-β expressed in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci,1993; 34:413．
32． Connor TB Jr, Roberts AB, Sporn MB, et al. Correlation of fibrosis and transforming growth factor-β type 2 levels in the eye. J Clin Invest, 1989; 83:1661．
33． Huang XQ, Mitchell MS, Liggett PE, et al. Non-fastidious, melanoma-specific CD8+ cytotoxic T lymphocytes from choroidal melanoma patients. Cancer Immunol Immunother, 1994; 38:399．
34． Niederkorn JY, Streilein JW. Induction of anterior chamber-associated immune deviation (ACAID) by allogeneic intraocular tumors dose not require splenic metastases. J Immunol, 1982; 128:2470．
35.Niederkorn JY. Suppressed cellular immunity in mice harboring intraocular melanomas. Invest Ophthalmol Vis Sci, 1984; 25:447.
36.Streilein JW, Niederkorn JY. Induction of anterior chamber-associated immune deviation requires an intact functional spleen. J Exp Med, 1981; 153:1058.
37.Knisely TL, Luckenbach MW, Fischer BJ, et al. Destructive and nondestructive patterns of immune rejection of syngeneic intraocular tumors. J Immunol, 1987;138:4515.
38.Niederkorn JY, Streilein JW. Lymphoma allografts abrogate immune privilege within the anterior chamber of the eye. Invest Ophthalmol Vis Sci, 1986; 27:1235.
39.Niederkorn JY. Exogenous recombination interleukin-2 abrogates anterior chamber-associated immune deviation. Transplantation, 1987; 43:523.
40.Miki S, Ksander BR, Streilein JW. Complete elimination of progressively growing intraocular tumors by local injection of tumor-specific CD8~+ T lymphocytes. Invest Ophthalmol Vis Sci, 1993; 34:3622.
41.Soiffer RJ, Chapman PB, Murray C, et al. Administration of R24 monoclonal antibody and low-dose interleukin 2 for malignant melanoma. Clin Cancer Res, 1997; 3:17.
42.Ma D, Niederkorn JY. Role of epidermal growth factor receptor in the metastasis of intraocular melanomas. Invest Ophthalmol Vis Sci, 1998; 39:1067.
43.Luckenbach MW, Streilein JW, Niederkorn JY. Histopathologic analysis of intraocular allogeneic tumors in mice. Invest Ophthalmol Vis Sci, 1985; 26:1368.
44.Schurmans LR, den Boer AT, Diehl L, et al. Successful immunotherapy of an intraocular tumor in mice. Cancer Res, 1999;59:5250.
45．孟宁，李志杰．眼内肿瘤与眼免疫赦免．中华眼底病杂志，2000；16：67．